© Commonwealth of Australia
This work is copyright. Apart from use permitted under the Copyright Act 1968, no part may be
reproduced by any process without prior written permission from the Australian Pesticides and
Veterinary Medicines Authority. Requests and inquiries regarding reproduction and rights should
be addressed to the Manager, Quality Assurance, Australian Pesticides and Veterinary Medicines
Authority, PO Box E240, Kingston ACT 2604, Australia or by email to MLS@apvma.gov.au
This document is published by the Australian Pesticides and Veterinary Medicines Authority (APVMA).
In referencing this document the APVMA should be cited as both the author and publisher.
ISBN 9780977576609
636.089510994
Information about the APVMA
The Australian Pesticides and Veterinary Medicines Authority (APVMA) is the Australian Government
statutory authority responsible for the registration, quality assurance and compliance of pesticides
and veterinary medicines up to and including the point of retail sale. Prior to their sale in Australia,
all agricultural and veterinary chemical products must be shown to work, be safe for people, animals,
plants and the environment, and not unduly jeopardise Australia’s trade with other nations.
The Australian Government and all states and territories have agreed to a National Registration
Scheme for Agricultural and Veterinary Chemicals. The Scheme sets out the regulatory framework for
the management of pesticides and veterinary medicines in Australia by a single agency. The APVMA
is responsible for managing and administering the Commonwealth’s regulatory responsibilities under
the National Registration Scheme.
The APVMA also manages a number of programs aimed at ensuring the safety and performance of
pesticides and veterinary medicines. One of these programs involves the licensing of manufacturers
of veterinary medicines.
The National Registration Scheme also provides for a national, uniform and cooperative legislative
regime for agricultural and veterinary chemicals throughout Australia administered by the APVMA.
The cooperative nature of the legislation is set out in the Agricultural and Veterinary Chemicals Act
1994 and complementary Agricultural and Veterinary Chemicals Acts of each state and territory. The
Agricultural and Veterinary Chemicals (Administration) Act 1992 lays down the governance principles
for the APVMA as an independent statutory authority of the Commonwealth. The centerpiece of the
Scheme’s legislation is the Agricultural and Veterinary Chemicals Code (the Agvet Code) scheduled
to the Agricultural and Veterinary Chemicals Code Act 1994. The Agvet Code provides the operational
details for the registration of chemical products by the APVMA as well as for quality assurance
and compliance programs for pesticides and veterinary medicines up to and including the point of
retail sale in Australia. Part 8 of the Agvet Code provides for the licensing of the manufacturers
of veterinary medicines by the APVMA, where the manufacturer complies with the APVMA’s
Manufacturing Principles.
Important Information 7
Manufacturing principles 9
Quality management guidelines 9
Management of quality 9
Quality assurance 9
Quality control 10
Quality and production nominees 10
Process control and change control 10
Manufacturing principles 11
Personnel and training guidelines 11
General 11
Key personnel 11
Qualifications and experience 12
Training and competency assessment 13
Personal hygiene and health issues 13
Manufacturing principles 15
Buildings and grounds guidelines 15
General 15
Cleaning and sanitation 16
Storage areas (including receipt and despatch) 17
Production areas 18
Quality control areas 19
Ancillary areas 19
Animal houses 19
Australian Code of Good Manufacturing Practice for Veterinary Chemical Products iii
CHAPTER 4 EQUIPMENT 21
Manufacturing principles 21
Equipment guidelines 21
General 21
Equipment qualification and validation 22
Maintenance 22
Calibration 22
Cleaning 23
CHAPTER 5 DOCUMENTATION 25
Manufacturing principles 25
Documentation guidelines 25
General 25
Document control 26
Records 27
Documents required 28
Specifications 28
Materials control (stores receipt, storage and disposal) 29
Master manufacturing formula, master batch records and
master manufacturing processing instructions 29
Master packaging and labelling instructions 30
Batch manufacturing/processing records 31
Batch packaging records 32
Quality control sampling and testing 33
Release/rejection and distribution of finished product 33
Complaints, recalls and returns 33
Computer records 34
Laboratory records 34
Validation records 34
Other 34
Manufacturing principles 35
Computer systems guidelines 35
General 35
Manufacturing principles 37
Production guidelines 37
General 37
Materials control (including storage) 37
General 37
Receipt, storage and quality assurance of raw materials 38
Receipt, storage and quality assurance of packaging materials 39
Cross-contamination control 39
Process validation 40
Production procedure 40
Dispensing of raw materials 40
Processing operations 40
Intermediate and bulk products 41
Process water 42
Primary (filling) and secondary packaging operations 42
Release of finished products 44
Residual, rejected, recovered and returned materials 44
Manufacturing principles 47
Quality control guidelines 47
General 47
Documentation 48
Sampling 49
Sampling plans 49
Sampling procedures 50
Retention samples 50
Product release 51
Manufacturing principles 53
Contract manufacture guidelines 53
General 53
The GMP Agreement 54
The contract giver 54
The contract acceptor 55
Inspection of contract manufacturers 56
Manufacturing principle 57
Internal audit guidelines 57
General 57
Manufacturing principles 59
Complaint and product recall guidelines 59
Complaints 59
Suspected product defects 60
Recalls 60
PART 2 ANNEXES 61
Important information 61
Manufacturing principles 63
Introduction 63
General 64
Premises 64
Production areas 64
Sanitation and hygiene 65
Environment control 65
Air quality 65
Environmental monitoring 68
Personnel 68
Equipment 69
Specification for materials 71
Processing 71
Sterilisation by heat—general 72
Sterilisation by moist heat 73
Sterilisation by dry heat 73
Sterilisation by radiation 73
Sterilisation by ethylene oxide 74
Sterilisation by filtration 74
Finishing (primary packaging) 75
Quality control 75
Aseptic processing 76
Manufacturing principles 81
Essential information 81
Premises 81
General 81
Segregation and containment 82
Sanitation, disinfection and waste disposal 83
Personnel 84
Equipment 84
Animals and animal houses 85
Production 86
General 86
Starting materials 86
Media 87
Seed lot and cell bank system 87
Operating techniques 87
Quality control 89
Introduction 91
Liquids, creams, pastes, gels and ointments 91
Powders and tablets 91
Products containing penicillins and other highly sensitising antibiotics 91
Electrolytes 91
Bloat oils 92
Slow-release intra-ruminal devices 92
Premises and equipment 92
Production 92
Australian Code of Good Manufacturing Practice for Veterinary Chemical Products vii
ANNEX 4 HERBAL PRODUCTS 93
Introduction 93
Premises 93
Storage areas 93
Documentation 93
Specifications for starting materials 93
ANNEX 5 ECTOPARASITICIDES 95
Introduction 95
Buildings and grounds 95
Manufacture 96
Introduction 97
Premixes and supplements 97
Introduction 97
Buildings and grounds 97
Personnel 98
Equipment 98
Process control 98
Mined mineral supplements 98
Direct-fed microbials and enzyme products 98
Introduction 98
Buildings and grounds 99
Personnel 99
Process control 99
Materials control 99
Production control 100
Enzyme recovery 100
GLOSSARY 101
viii Australian Code of Good Manufacturing Practice for Veterinary Chemical Products
Introduction
Veterinary chemical products are subject to a registration process that requires them to be fit for
their intended use and to not place treated animals or users at risk due to inadequate safety, quality
or efficacy. Veterinary chemical products must be manufactured in such a way that they comply with
their registered particulars and that there is batch-to-batch consistency.
The ultimate responsibility for attaining these quality objectives lies with senior management, but
their attainment also requires the participation and commitment of all staff, at all levels, within
the manufacturing organisation. In order to achieve these objectives, the manufacturer must have
in place a comprehensively designed, adequately resourced and correctly implemented system of
quality assurance, incorporating the principles of good manufacturing practice (GMP).
Quality assurance is a wide-ranging concept covering all aspects of the manufacturing process that
individually or collectively influence the quality of a manufactured product. It is the sum total of the
arrangements made to ensure that veterinary chemical products are consistently manufactured in
an appropriate manner to the quality standards required for their intended use. Quality assurance
therefore incorporates both GMP and quality control as well as other factors outside the scope of this
Code of GMP such as environmental and occupational safety controls.
The quality management system must be relevant to the needs of the product. It must be fully
documented, monitored for effectiveness and incorporate an element of continuous improvement.
Good manufacturing practice (GMP) is the part of quality assurance that ensures that products
are consistently manufactured to the quality standards appropriate for their intended veterinary use
and in accordance with their registration particulars and specifications. GMP is concerned with both
production and quality control. It is a means of giving consumers confidence that the products meet
the required quality standards and are safe and reliable for the purposes for which they are intended.
(a) all manufacturing processes are clearly defined, are systematically reviewed in the light of
experience, and shown to be capable of consistently producing veterinary chemical products that
comply with their specifications and the required quality standards
(b) critical steps of manufacturing processes and significant changes to the processes are validated
(c) all necessary facilities for GMP are provided, including:
(i) appropriately qualified, trained or experienced personnel
(ii) adequate premises and space
Quality control is the part of GMP that is concerned with specifications, sampling and testing, and
with the organisation, documentation and release procedures that ensure that the necessary and
relevant tests are carried out so that materials are not released for use, nor products released for
sale or supply, until their quality has been judged to be satisfactory.
Compliance with GMP ensures that quality is built into the product at the time of manufacture. It
requires products to be consistently manufactured in a safe and clean environment, by specified
methods, under adequate supervision, with effective quality control procedures, and with a
documentation trail that links starting materials, through the various manufacturing processes, to the
finished product.
The various codes of GMP provide guidance as to what is required to achieve acceptable standards
for manufacturing and handling veterinary chemical products. Such codes have been adopted in
many other countries and are fundamental to maintaining the quality of veterinary preparations in
international trade.
This revised Australian Code of Good Manufacturing Practice for Veterinary Chemical Products replaces
both the Australian Code of Good Manufacturing Practice for Veterinary Preparations and the Australian
Code of Good Manufacturing Practice for Homemixed Feeds, Feed-Milling Industry Stockfeed Premixes,
which have formed the basis of the APVMA’s Manufacturers’ Licensing Scheme since its inception
in March 1996. Unlike these earlier Codes, which provided different codes for different types of
products, the core chapters of this revised Code of GMP apply to all types of products and to all types
of manufacturing plants. The annexures describe any additional or specialised requirements relating
to specific types of products, such as immunobiological and sterile products, ectoparasiticides,
and premixes.
The intent of each core element has been clearly defined at the start of the relevant chapter in
the form of a ‘manufacturing principle’. This will clarify the intent (or objectives) of each element
of the GMP Code and facilitate more consistent interpretation. These manufacturing principles will
To facilitate exports, this Code of GMP has been aligned with the Guide for Good Manufacturing
Practice for Medicinal Products, September 2003 edition, published by the Pharmaceutical Inspection
Convention Cooperation Scheme (PIC/S), which is increasingly being used by many of Australia’s
overseas trading partners, such as New Zealand, some Southeast Asian countries and Europe.
This is also the code that is followed by Australian veterinary chemical manufacturers who also
manufacture human pharmaceutical products.
The APVMA’s revised GMP Code has been written specifically to meet the needs of all Australian
veterinary chemical manufacturers. Despite the amalgamation of two codes into one, and alignment with
the PIC/S code, many of the requirements of the original codes have remained essentially unchanged.
An APVMA survey of veterinary chemical manufacturers in 2002 revealed industry support for a single
code of GMP that was applicable to all sectors of the industry, but which also identified any special
requirements that were specific to particular sectors (e.g. the manufacture of immunobiological and
sterile products, ectoparasiticides, and premixes). There was also support for a code that was more
closely aligned with the PIC/S Code, which would facilitate exports to countries that have adopted
that GMP code (e.g. New Zealand, some Southeast Asian countries, and Europe) and that would also
meet the particular requirements of the Australian veterinary chemical industry.
• Part 1 deals with the basic principles or core elements of GMP and applies to all sectors of the
industry, all types of products and all sizes of manufacturing plant.
• Part 2 contains the Annexes. These describe additional or modified requirements and guidelines
for specific sectors of industry, such as manufacturers of sterile and immunobiological products,
ectoparasiticides, premixes and supplements. These Annexes supplement the core elements
in Part 1. They do not replace them, and should be read and applied in conjunction with the
relevant core elements.
The intent of each core element is described in the manufacturing principle(s) at the start of each
chapter and all manufacturers are required to comply with these principles. The guidelines for each
chapter provide guidance as to what manufacturers are expected to do in order to comply with the
relevant manufacturing principle(s). Additional guidance material is provided in documents such as
the European Pharmacopoeia, international and Australian standards, PIC/S guidelines and other
relevant reference material, and manufacturers are expected to refer to such references where
appropriate.
The revised GMP Code places greater emphasis on the need for manufacturers to maintain
an effective quality assurance function and to periodically undertake a scientifically based risk
assessment of their processes and procedures. In this regard, it is expected that manufacturers will
embrace a culture of continuous improvement and that manufacturing practices will be progressively
updated in line with technological developments.
The guidelines in the GMP Code are generally expressed in terms of ‘should’ and provide some
element of flexibility. That is, manufacturers may use an alternative way of satisfying a particular
guideline, provided they can demonstrate, on rational scientific grounds, that they meet the intent of
the relevant core element. This is particularly important for small manufacturers and manufacturers
of products that are not normally thought of as pharmaceutical, such as anti-bloat preparations
sprayed onto pastures, salt licks, mined mineral supplements such as dolomite and limestone,
therapeutic pet foods and some intra-ruminal devices. In those situations, the way in which the
Manufacturing Principles are met might be quite different from what is done in a conventional
pharmaceutical plant. For example, a small owner-operated business would not be expected to have
an organisational chart or to have a separate person responsible for quality. However, it would be
expected to have a suitably qualified/experienced person to release products in accordance with
clearly defined and documented procedures.
In all cases, the nature and intended use of the product should be taken into account when
interpreting the GMP Code, as well as the need to meet consumer expectations for a safe and
Exempt persons or products are defined in Regulation 59 of the Agricultural and Veterinary Chemicals
Code Regulations 1995.
Core Code Of GMP
CHAPTER 1
Quality Management
Manufacturing principles
• Manufacturers of veterinary chemical products must have in place a quality assurance system to
ensure that finished products are fit for their intended use, comply with registration requirements
and do not place treated animals or users at risk due to inadequate quality, safety or efficacy.
• The quality assurance system must ensure that:
– appropriate procedures are in place to ensure that relevant quality standards are met
– all materials involved in the manufacturing process comply with required quality standards
before they are released for use in manufacture
– there are measures designed to prevent cross-contamination
– there are safeguards and controls in place designed to prevent the occurrence of
foreseeable errors or process failures
– finished products have been made and stored correctly, and they comply with required
quality standards before they are released for supply.
• The quality assurance system must be relevant to the nature and intended use of the product. It
must be fully documented, monitored for effectiveness and provide for continuous improvement.
Quality assurance
104 The quality assurance system should ensure that:
(a) managerial responsibilities are clearly defined, documented and exercised
(b) production and control operations are clearly specified and good manufacturing and
good laboratory practices are followed
(c) starting and packaging materials meet required specifications utilising, where possible,
vendor assurance
(d) all necessary controls on intermediate products and in-process controls are
carried out
Quality control
105 A system of quality control should be in place to ensure that products comply with their
required specifications and standards. The basic requirements of that quality control system
are described in Chapter 8.
107 The persons responsible for Production and Quality should have effective control over any
manufacturing steps carried out at all premises covered by the manufacturing licence.
108 The person nominated as having responsibility for Production must have the necessary
authority to control manufacture of the product. The usual duties of that person are
described more fully in Chapter 2.
109 The person nominated as having responsibility for Quality must have the necessary
independence and authority to ensure that quality measures are employed in the production
and testing of the product and that the product is not released until it has been judged to be
satisfactory. The usual duties of that person are described more fully in Chapter 2.
110 Where operational events and quality policy conflict, the person nominated as having
responsibility for Quality must have the authority to make a decision to resolve the conflict.
The circumstances and the decision must be recorded.
112 A change control system should be in place to manage significant manufacturing and
product quality changes. This should include application to APVMA, as the registration
authority, to vary product details where necessary.
Chapter 2
Personnel AND Training
Manufacturing principles
• Veterinary chemical products must be manufactured under the management and supervision of
appropriately qualified, trained or experienced persons who:
– understand the specialised technical, quality and legal requirements relating to the
manufacture of veterinary chemical products for which they have responsibility
– have their duties and responsibilities clearly defined by the manufacturer.
• Manufacturing staff must be trained to a satisfactory level of competency in:
– the basic principles of good manufacturing practice
– the specific duties, in connection with the manufacture of veterinary chemical products, that
they are required to perform.
• There must be a sufficient number of competent personnel to carry out all required tasks.
202 The manufacturer should have an organisational chart showing the names of key personnel,
as well as their areas of responsibility and lines of authority.
203 People in responsible positions should have written job descriptions describing their specific
duties. There should be no gaps or unexplained overlaps in the responsibilities of those
personnel concerned with the application of GMP.
204 People in responsible positions must have adequate authority to carry out their
responsibilities.
205 The duties of persons in responsible positions may be delegated to designated deputies
with relevant qualifications and experience. Records should be kept of those delegations.
206 Operators’ verbal and written communication skills should be sufficient for them to respond
to training, accept and implement instructions exactly and, where their duties require it, fill
out forms correctly.
Key personnel
207 Key personnel include the persons nominated as responsible for Production and for Quality
and, if neither of these persons is responsible for product release, the person(s) authorised
for that purpose. Normally, key positions should be occupied by full-time personnel.
208 The persons responsible for Production and for Quality should be independent from each
other. In small operations where this may not be possible, the quality control function and
procedures should be clearly documented and shown to be effective.
209 The person with overall responsibility for Production usually has responsibility to:
(a) ensure that products are produced and stored according to documented procedures
(b) approve procedures relating to production operations and ensure their strict
implementation
(c) approve and monitor any subcontracted production work
(d) ensure that production records are evaluated and signed by an authorised person
before they are submitted for product release
(e) ensure that production areas, premises and equipment are maintained to an
appropriate standard
(f) ensure that appropriate validations are conducted
(g) ensure that initial and continuing training of production personnel are conducted,
according to need.
210 The person with overall responsibility for Quality usually has responsibility to:
(a) evaluate and authorise master manufacturing and packaging documents
(b) approve specifications, sampling instructions, test methods and other quality
control procedures
(c) approve or reject raw materials, packaging materials, and intermediate, bulk and
finished products
(d) review completed batch records as part of the release procedures
(e) ensure that all necessary testing is carried out
(f) approve and monitor any contract analysts
(g) monitor quality performance of subcontract manufacturers
(h) check the maintenance of the quality control area, premises and equipment
(i) ensure that appropriate validations are conducted
(j) ensure that initial and continuing training of quality control personnel are conducted,
according to need
(k) approve and monitor the suppliers of materials.
211 In some cases, the persons responsible for Production and Quality may have some shared
or jointly-exercised responsibilities provided their primary roles are not compromised.
214 Training programs should be appropriate to the identified needs of staff and be approved by
the head of either Production or of Quality, as appropriate. The effectiveness of the training
program should be monitored.
215 Training programs should include initial training in the basic principles of GMP, as well as
training appropriate to the duties assigned to staff. Programs should also include ongoing
training and refresher training, including training in changes to the manufacturing process
and procedures. Training programs should specifically address the concept of quality
assurance, as well as relevant aspects of sanitation and personal hygiene.
216 Records should be kept of all internal and external training programs and the various
training activities undertaken by individual staff.
217 Staff should be assessed for their competence to perform the duties assigned to them.
Records should be kept of those assessments.
218 Personnel working in areas where contamination is a hazard (e.g. cleanrooms or areas
where highly active, toxic, infectious or sensitising materials are handled) should be given
specific training in those aspects of manufacture.
220 Personnel should not be required, or allowed, to sign or initial a document unless they
have been trained and assessed as competent in the work practices associated with the
signature and in the significance of the signature.
221 A register of staff signatures and initials should be maintained. Entries should be updated
at regular stated intervals and the previous records archived.
222 Visitors or untrained personnel preferably should not be taken into active production and
quality control areas. If access is unavoidable, they should be adequately supervised and
be given information in advance, particularly about personal hygiene and prescribed
protective clothing.
224 Where relevant, production personnel should be subjected to medical examination to ensure
that their health status does not pose a risk to product quality and that they are able to
carry out required tasks (e.g. visual checks of labels or containers).
225 Staff should be made aware of the need to draw management’s attention to any health
problems that might affect product quality. Steps should be taken to ensure that anyone
affected by an infectious disease, or having open lesions on an exposed surface of the
body, is not engaged in activities where operator-borne contaminants may pose a risk to
product quality.
226 Every person entering the manufacturing or quality control areas should wear protective
garments appropriate to the operations carried out there.
227 Protective clothing should be cleaned and/or replaced at fixed intervals or when
soiled. It should be kept in good condition. When necessary, soiled clothing should be
decontaminated before being laundered (e.g. clothing from areas where live microorganisms
are being cultured). Where garments are laundered off-site, any special precautions required
to avoid harm to personnel or the environment should be specified. Protective clothing
should not be worn outside the factory premises.
228 Eating, drinking, chewing, smoking, or the storage of food, drink, smoking materials
or personal medication must not be allowed in the production, packaging, storage, or
laboratory areas. Relevant signs should be displayed at prominent positions at entry points
to these areas.
229 Direct contact should be avoided between the operator’s bare hands and the exposed
product or any part of the equipment that comes into contact with the product.
230 The wearing of jewellery that may become detached or caught in machinery should be
discouraged in manufacturing areas.
231 Specific hygiene requirements for the manufacture of special groups of products
(e.g. immunobiologicals and sterile products) are covered in the relevant annexes.
Chapter 3
Buildings AND Grounds
Manufacturing principles
• Veterinary chemical products must be manufactured in buildings that are located, designed,
constructed, maintained and utilised to:
– suit the operations carried out in them
– ensure protection of the veterinary chemical products from contamination
– permit effective cleaning and maintenance, including cleaning after processes have been
completed
– minimise the risk of manufacturing error.
• The products must also be manufactured in an environment, or in equipment fitted with
precautionary measures, that:
– ensures a standard of hygiene appropriate to the class of veterinary chemical product being
manufactured
– minimises the risk of cross-contamination of the finished product, or of materials or
components that are used or manufactured at the premises
– ensures the safety of operators and protects the outside environment.
302 The premises, including the surrounding grounds and gardens, should be kept in an orderly,
neat and tidy condition.
303 Premises should be designed, constructed and maintained to minimise the effects of
weather and ground seepage, the entry and accumulation of dust and other airborne
materials, and the entry of insects, birds, rodents, vermin and other animals. Cavities and
voids should be minimised and, where necessary, provided with access for pest control
purposes.
304 Each part of the premises should be suitable for the operations being carried out and be
kept in good repair. Repair and maintenance operations should not present any hazard to
product quality.
305 Lighting, temperature, humidity and ventilation should be appropriate for the type of
operations being undertaken. They should not directly or indirectly, adversely affect product
quality during manufacture and storage, or the accurate functioning of equipment. Air
intakes should be located away from sources of contamination.
306 Sinks should be made of stainless steel, without overflow and preferably be spaced
50 mm away from walls so as to avoid uncleanable joins and crevices. They may require
effective, easily cleanable traps and have air breaks to prevent backflow.
307 Floor drains should generally be avoided, as they are a potential source of contamination.
Where they are necessary, they should be of adequate size, flush with the floor, screened
and trapped. Drains should generally be underground. Open channels should be avoided,
but, if necessary, should be shallow to facilitate cleaning and disinfection.
308 Production and quality control areas should not be used as passageways by personnel who
do not work in them, or for the transport of materials not being currently used in them. They
should not be used as storage areas for obsolete materials or equipment.
309 The premises should be secured against entry of unauthorised personnel or materials.
Visitors to the premises, including external maintenance workers and contractors, should be
supervised and restricted to an appropriate level of access.
311 Documented cleaning procedures should be available for all areas. These should describe:
(a) the areas to be cleaned, the frequency of cleaning, and specific requirements of
individual areas
(b) the materials, concentrations and equipment to be used
(c) the methods used to decontaminate cleaning equipment.
312 Where the removal of traces of product is critical, evidence to demonstrate that the cleaning
process is effective should be available. In these cases, unless standards of cleanliness
are prescribed by a regulatory authority, manufacturers should determine appropriate limits
based on assessed risk.
313 Waste material should be deposited in suitable, appropriately located and labelled
containers and appropriately disposed of at frequent intervals. Where necessary, effluent
should be treated before disposal.
314 The premises should be kept free of insects, birds, rodents, and other animals, either by
containment or by appropriate control measures. A documented pest control program should
be in place, which should be monitored for effectiveness. Records should describe the
location of bait stations, materials used, monitoring frequency and effectiveness.
316 Storage areas should provide storage conditions appropriate to the materials and products
held in them. In particular, they should be clean, dry, and maintained within acceptable
temperature limits. Where special storage conditions are required
(e.g. temperature and humidity) these should be provided and monitored. However, these
requirements do not preclude outdoor storage of materials where outdoor storage does not
adversely affect quality.
317 Where a controlled storage temperature is critical for the maintenance of material or product
quality, the environment should be controlled, monitored and recorded, as follows:
(a) there should be temperature recording devices, and records should be under
regular review
(b) there should be an alarm and/or visual signal to indicate that a storage temperature
control system has failed; the system should permit resetting only by authorised
personnel and should be checked at regular, stated intervals.
318 Refrigerators, cold rooms and freezers should be regularly defrosted and cleaned. In the
event that a refrigeration storage facility is shut down, total cleaning should occur.
319 Receiving and despatch bays should protect materials and products from the weather and
should be designed and equipped to allow containers of incoming materials to be cleaned,
where necessary, before storage.
320 On receipt, all starting materials (including labels, printed cartons and other packaging
material) should be subject to effective quarantine and release control.
321 Where quarantine status is ensured by storage in separate areas, these areas should be
clearly marked. Any system replacing a physical quarantine system (such as a computerised
access system) should provide at least an equivalent level of security.
322 Sampling of raw materials should be conducted in such a way that contamination of
the material, or cross-contamination of other materials, is prevented. There should be a
separate sampling area for highly active, hazardous or toxic raw materials.
323 Highly active, hazardous or toxic materials or products, or otherwise incompatible materials
should be stored in such a way as to not pose a risk to other materials or products.
324 Labels should be stored in segregated areas with restricted access. Other pre-printed
packaging materials should be stored in such a way as to prevent mix-up.
Production areas
325 The operations carried out in any particular area should be compatible so that the integrity
of any product made in the area is not threatened.
326 Manufacture of sterile, highly active, toxic or infective products should normally be
performed in dedicated, self-contained facilities. Processes that may give rise to significant
risk from cross-contamination may also require such facilities. However, campaign
manufacture in the same facilities may be accepted, provided that specific, documented
precautions are taken.
327 Registered veterinary chemical products should not be manufactured in the same areas as
poisonous, toxic or hazardous unregistered consumer products.
328 Veterinary chemical products containing technical poisons should be handled in segregated
areas or separate buildings, usually with equipment dedicated to this class of product.
However, common areas or equipment may be accepted, provided that cross-contamination
is controlled by scheduling or use of a validated cleaning procedure.
329 Premises should be laid out in a way that allows the orderly and logical positioning of
equipment and materials so as to minimise the risk of confusion between different
veterinary chemical products or their components, to avoid cross-contamination and to
minimise the risk of omission or wrong application of any of the manufacturing or
control steps.
330 Where starting and primary packaging materials, or intermediate or bulk products are
exposed to the environment, interior surfaces (walls, floors and ceilings) should be suitable
for the class of product being manufactured. This will usually require surfaces that are
nonporous, smooth, free from open joints, and do not shed particulate matter. They should
also permit effective cleaning.
331 Joins between walls and floors should be easy to clean, adequately sealed and where
appropriate, coved to form a smooth curve between the floor and wall.
333 The use of wood-based pallets should be avoided in production areas where there is a risk
of contamination of the product.
334 Pipe work, light fittings, ventilation points and other services should be designed and
located to avoid the creation of recesses that are difficult to clean. As far as practicable,
they should be accessible from outside the manufacturing areas for maintenance purposes.
335 Production areas should be effectively ventilated and allow, where necessary, control of air
flow, temperature, humidity and filtration appropriate to the products handled, the operation
undertaken and the external environment.
336 The arrangements for weighing or measuring raw materials should minimise cross-
contamination. This may require the use of separate weighing or dispensing rooms designed
and reserved for that use. Dispensing rooms should not be used as storage areas for
starting and other materials.
337 Where dust is generated (e.g. during sampling, weighing, mixing and processing operations,
or packaging of dry products), specific provision should be made and precautions taken, to
avoid cross-contamination (e.g. efficient dust extraction, use of dedicated enclosed areas)
and to facilitate cleaning.
338 Materials likely to shed fibres or other contaminants, such as wooden pallets or fibreboard,
should not be taken into areas where products or clean containers are exposed.
339 Production areas should be well lit, particularly where visual on-line controls are
carried out.
341 Quality control laboratories should be designed to suit the operations carried out in them.
Space should be sufficient to avoid mix-ups and cross-contamination. There should be
adequate storage for samples and records.
342 Sensitive instruments should be protected from adverse effects such as vibration, electrical
interference, and humidity.
Ancillary areas
343 Staff amenities, including lunch rooms, should be separate from storage, production and
quality control areas.
344 Clean and well-ventilated toilets and changing rooms should be provided. These should be
easily accessible and suitably isolated from any production, quality control or storage areas.
They should be appropriate for the number of users and should be maintained in a tidy and
hygienic manner, with an adequate supply of hot and cold water, soap and hygienic hand-
drying facilities.
345 A sufficient number of clean hand basins, with a satisfactory supply of hot and cold water,
soap or detergent dispensers, and hygienic hand-drying facilities should be provided near
working areas for use by production personnel.
346 Maintenance workshops should, as far as possible, be separate from production areas.
Whenever parts or tools are stored in the production area, they should be kept in rooms or
lockers reserved for that use.
Animal houses
347 Areas in which animals are housed should be adequately isolated from storage and
processing areas, with separate access for animals and separate air handling facilities.
Chapter 4
Equipment
Manufacturing principles
• Equipment used in the manufacture of veterinary chemical products must be suitable for its
intended purpose and appropriately operated, maintained and cleaned. Equipment must be
correctly installed and operated in accordance with written instructions that are appropriate for
the equipment.
• The design and layout of equipment must be such that:
– the risk of manufacturing error is minimised
– effective cleaning and maintenance are possible, in order to avoid cross-contamination
of either intermediate materials or the finished product, the buildup of dust or dirt and, in
general, to avoid any adverse environmental effect on the quality of the product.
Equipment guidelines
General
401 Equipment used for the manufacture (including testing) of veterinary chemical products,
should be designed, located and maintained to suit its intended purpose and should
be installed and positioned in such a way as to minimise any risk of error or cross-
contamination.
402 Equipment should be used in accordance with written instructions that are appropriate to
the equipment and consistent with any operating instructions issued by the equipment
manufacturer.
403 Production equipment should not present any hazard to the manufactured products
(e.g. by contamination of processed materials or finished products, or their containers,
with lubricants or other extraneous substances). The parts of the production equipment
that come into contact with materials being processed or the finished product must not be
reactive, additive, or absorptive to such an extent that product quality is adversely affected.
404 Equipment should be uniquely identified. This identification should be traceable to all
records pertaining to the equipment.
405 If prone to failure or variance, equipment used for critical steps in the manufacturing
process should be monitored by devices capable of recording the necessary operating
parameters, or should be equipped with alarm devices to indicate malfunction. If such
devices are not practical, the output should be monitored to ensure early detection
of variance.
406 Balances and other measuring equipment required for production and quality control
operations should be available and should have an appropriate range and degree of
precision. Equipment should be properly positioned before use.
407 Fixed pipework should be clearly labelled to indicate the contents and, where applicable, the
direction of flow. Pipes should be adequately sloped for drainage and constructed without
‘dead-legs’. There should be measures in place to ensure that materials transferred via
pipelines are delivered to the correct destination.
408 Defective equipment should, if possible, be removed from production and quality control
areas, or be clearly labelled as defective.
410 Equipment that has been taken out of service, modified or undergone major repairs should
be formally approved for re-entry into service.
Maintenance
411 All equipment should be properly maintained and records of this maintenance should be
kept. In addition, equipment should be inspected for serviceability before any operation
begins.
412 Repair and maintenance operations should not present any hazard to product quality.
Calibration
414 Each item of equipment used in manufacture or for quality control purposes that measures
or depends on a physical parameter (e.g. measuring, weighing, recording and control
equipment), should be calibrated at defined intervals, in accordance with a written
procedure. That procedure should describe the method and frequency of calibration or
observation, taking into account any statutory requirements, as well as the action to be
taken when results deviate from defined acceptance limits.
415 Where appropriate, verification checks should be performed at a frequency consistent with
the use of the equipment, in accordance with a written procedure.
416 Records should be kept of any calibrations, verification checks or observations carried
out on such equipment. Those records should contain sufficient information to show that
the required calibrations/observations have been carried out and provide details of any
necessary corrective action taken.
417 Records of any equipment calibration should show the actual results observed and the
acceptance criteria.
418 Where practicable, each item requiring calibration should bear a label or tag indicating
that calibration has been carried out and when the next calibration is due. Alternatively, a
computer-based maintenance system that flags the need for calibration can be accepted,
provided that it can be shown to be working effectively.
419 There should be evidence to demonstrate that the particular calibrating devices used
are themselves accurate. Contractors who calibrate equipment should be certified by a
certification agency.
Cleaning
420 Manufacturing equipment should be designed so that it can be easily and thoroughly
cleaned. Where necessary, it should be easily dismantled for cleaning. It should be cleaned
according to detailed written procedures, and only stored in a clean, dry environment.
Records should be kept of equipment cleaning operations.
421 To facilitate cleaning, equipment should be mobile or clear of walls and floors. Where this is
not practical, equipment should be sealed to the surfaces it touches.
422 Permanently fixed product and process-water pipelines should have sanitary couplings and
be sloped for drainage.
423 Washing and cleaning equipment should be chosen and used in such a way that it is not a
source of contamination.
424 Pipes for distilled, purified and, where appropriate, other water should be sanitised according
to written procedures that detail the action limits for microbiological contamination and the
measures to be taken if action limits are exceeded.
425 Equipment should be cleaned to the frequency and extent necessary to preserve product
integrity. A cleaning record should be kept either on the batch record or in an equipment
log book.
426 Validation of cleaning procedures should be considered where traces of ingredient may pose
significant contamination or toxicity risk in following product batches.
CHAPTER 5
Documentation
Manufacturing principles
• Manufacturers of veterinary chemical products must establish and maintain a system of
documentation, document control and record keeping that:
– provides precise specifications for starting materials, intermediate materials and finished
products, manufacturing formulae and instructions, and operating procedures for associated
manufacturing and quality control activities
– provides a complete history of each item, batch, or quantity manufactured in a specified
timeframe, of veterinary chemical product produced at the premises
– establishes a traceable connection between raw materials and the finished product.
Documentation guidelines
General
501 All processes and associated activities in the manufacture of veterinary chemical products
should be documented and the documents subjected to a system of
document control.
502 Manufacturing documentation should be designed, prepared, reviewed and distributed with
care. It should comply with the relevant parts of product registration dossiers and registered
particulars for the product and should be regularly reviewed and kept up to date.
503 Documents should be approved, signed and dated by appropriate and authorised persons.
In the case of master manufacturing formulae, manufacturing instructions, and packaging
and labelling instructions, a second authorised person should check, reconcile, endorse and
date both the formula and instructions.
504 Issue of working documents and forms should be limited to photocopying from current,
authorised, signed, hard master documents or printing from access-controlled authorised
electronic versions.
505 Documents should be legible, readily identifiable and retrievable. They should not include
superfluous data and, at the working level, should be written in the imperative (i.e. as
instructions rather than statements of what is desired). They should be laid out in an orderly
fashion and be easy to check.
506 Documents should not be handwritten. Data entries may be handwritten or machine-printed,
and must be clear, legible and permanent. Sufficient space should be provided for such entries.
507 The contents of documents should be unambiguous. The title, nature and purpose should
be clearly stated. The document should clearly identify the way in which it is to be used, and
by whom it is to be used. It should include, or be identifiable to, the issuing premises and
should also include the following information:
(a) a unique number identifying the document
(b) the version number and date it became effective
(c) the page number of the total number of pages of the document on each page
(d) provision for authorisation.
509 Reproduced documents should be clear and legible. The reproduction of working documents
from master documents (e.g. by photocopying or by computer printout), should not allow
error to be introduced through the reproduction process. A designated competent person
should initial each reproduced document before issue to signify that it is complete, legible
and appropriate.
510 Any correction to a document should permit the reading of the original information.
Corrections should be handwritten clearly and legibly in permanent ink, and initialled and
dated by an authorised person. Where appropriate, the reason for the alteration should
be recorded.
511 Where appropriate, new or revised documents should be introduced following a formal
commissioning and training period.
Document control
512 The system of document control should be documented. That document should define the
procedures in place for:
(a) approval and regular review of documented procedures
(b) distribution of documents
(c) removal of obsolete documents from all points of issue and use
(d) prevention of inadvertent use of superseded documents.
513 A documented procedure should be in place that defines the controls needed for the
storage, protection, retrieval, retention time and disposal of records.
514 The system of document control should include a list of all controlled documents and should
identify the current revision status of any controlled document and the holder/location of
that document.
515 Changes to controlled documents should be acted upon promptly. They should be reviewed,
dated and signed by the authorised person(s) and formally implemented. There should be
records to show that all relevant personnel have acknowledged subsequent changes to
procedures.
516 Where key documents (e.g. master manufacturing formulae or master manufacturing
instructions, critical cleaning procedures) have been revised, all associated or linked
documents (e.g. batch manufacturing instructions, batch documentation) should be updated
to reflect any relevant changes to the key documents, or be otherwise linked to the revised
documents.
Records
517 Records should be made or completed at the time each action is taken.
518 Manufacturing records must be retained by the manufacturer for the period specified in the
Agricultural and Veterinary Chemicals Code Regulations 1995, as cited below.
(a) the materials used in the manufacture of the chemical products, the supplier and
quantities of the materials used and details of the tests performed on those materials;
and
(b) the procedures and controls employed in the manufacture of the chemical products,
including the results of tests carried out during the processing of the chemical products;
and
(c) details of tests performed on the chemical products and the results of those tests; and
(d) the stability studies (if any) that validate the recommended shelf life and appropriate
storage conditions of the chemical products.
Regulation 61(5) A holder of a licence must keep at the premises to which the licence relates:
for at least 12 months after the expiry date of the products to which they relate or, if there is no
expiry date, for at least 6 years after the date on which the manufacture of the products was
completed.
519 Data may be recorded by electronic data processing systems, photographic or other reliable
means, but detailed procedures relating to the system in use should be available and the
accuracy of the records should be checked.
520 If documentation is handled by electronic data processing methods, only authorised persons
should be able to enter or modify data in the computer and there should be a record of
changes and deletions. Access should be restricted by passwords or other means. See
Chapter 6 (Computer Systems) for details.
521 Batch records that are stored electronically should be backed up by suitable means on a
regular basis. It is particularly important that the data are readily available throughout the
period of retention.
522 Consideration should be given to storage of batch records and other critical records in a
safe and secure environment.
Documents required
Specifications
523 There should be authorised and dated specifications for starting and packaging materials,
as well as finished products, appropriate for the type of product being made and consistent
with data submitted for product registration. Where appropriate, they should also be
available for intermediate or bulk products.
524 Specifications for starting and primary or printed packaging materials should include, where
applicable:
(a) a description of the materials, including:
(i) the designated name and the internal code reference
(ii) the reference, if any, to a pharmacopoeial monograph, or any other document on
which the specification is based
(iii) the approved source of any active material
(iv) the preferred suppliers; and, if relevant, the original producer of the materials
(v) a specimen of printed materials
(b) directions for sampling and testing, or reference to procedures
(c) qualitative and quantitative requirements with acceptance limits
(d) storage conditions and precautions
(e) the maximum period of storage before re-examination
(f) any relevant safe handling instructions.
525 Where specifications for raw materials are based on a valid certificate of analysis
provided by a supplier, a copy of that certificate of analysis should be suitably identified
and authorised by an appropriate person and retained as part of the manufacturer’s
specifications.
526 Specifications for intermediate and bulk products should be available if these are purchased
or despatched, or if data obtained from intermediate products are used for the evaluation of
the finished product. The specifications should be similar to specifications for raw materials
or for finished products, as appropriate.
(a) the name of the material on the delivery note and the containers
(b) the ‘in-house’ name and/or code of material if different
(c) date of receipt
(d) supplier’s name and, if possible, manufacturer’s name
(e) original manufacturer’s batch or reference number
(f) total quantity, and number of containers received
(g) the unique identifying number (UIN) assigned by the licensed manufacturer
after receipt
(h) any relevant comment (e.g. state of the containers).
The records should include the date of release by either Quality Control or an authorised,
competent person.
531 There should be written procedures for the internal labelling (including status labelling
to indicate whether under test, quarantined, passed for use or rejected), quarantine and
storage of raw materials, packaging materials and other materials, as appropriate.
532 Any special storage requirements (e.g. temperature) for individual materials should be
documented. Records should be kept to confirm that materials have been kept under
appropriate storage conditions.
534 The master manufacturing formula and master manufacturing instructions should be
prepared, endorsed and dated by a competent person delegated by management. A second
authorised person should check, endorse and date the instructions where possible. They
should be kept up to date at all times and reviewed at specified intervals not exceeding
three years. Any amendments should be checked by a second competent person.
538 The master packaging and labelling instructions should be prepared, endorsed and dated
by an authorised person. An authorised second person should check, endorse and date
the instructions, where possible. Instructions should be kept up to date at all times and
reviewed at intervals of no longer than three years. Any amendments should be checked by
an authorised second person.
539 The master packaging and labelling instructions should normally include, or have a reference
to, the following:
(a) name of the product
(b) description of its pharmaceutical form, and strength, where applicable
(c) the pack size, expressed in terms of the number, weight or volume of the product in the
final container
(d) a complete list of all the packaging materials required for a standardised batch size
and, where required, an actual batch size, including quantities, sizes and types, with the
code or reference number relating to the specifications of each packaging material
(e) where appropriate, an example or reproduction of the relevant printed packaging
materials or labels, or the APVMA label approval number(s)
(f) special precautions to be observed, including a careful examination of the area and
equipment, in order to ascertain the line clearance before operations begin; any
relevant scheduling and/or special cleaning instructions; and any relevant safety
precautions
(g) a description of the packaging operation, including any significant subsidiary operations,
and equipment to be used
(h) details of in-process controls, with instructions for sampling and acceptance limits
(i) the approved shelf life
(j) provision for calculation of batch yield
(k) provision for label reconciliation.
541 During processing, information should be recorded at the time each action is taken and,
after completion, the record should be dated and signed showing agreement by the person
responsible for the processing operations. The information to be recorded includes:
(a) dates and times of commencement of significant intermediate stages and of
completion of production
(b) name of the person responsible for each stage of production
(c) initials of the operator of each significant step of production and, where appropriate, of
the person who checked each of these operations
(e.g. weighing)
(d) the UIN, as well as the quantity of each starting material actually weighed (including the
batch number and amount of any recovered or reprocessed material added)
(e) a record to confirm that the equipment and workstation are clear of previous products,
documents or materials not required for the planned process, and that equipment is
clean and suitable for use
(f) any relevant processing operation or event and major equipment used
(g) a record of the in-process controls, the initials of the person(s) carrying them out, and
the results obtained
(h) the final product yield, as well as yields obtained at pertinent stages of manufacture
(i) notes on special problems, including details, with signed authorisation, for any planned
deviation from the manufacturing formula and processing instructions and authorisation
for processing to continue in the event of unplanned deviations.
543 Before any packaging operation begins, there should be recorded checks that the equipment
and workstation are clear of previous products, documents or materials not required for
the planned packaging operations, and that equipment is clean and suitable for use (line
clearance).
544 The following information should be entered at the time each action is taken and, after
completion, the record should be dated and signed showing agreement by the person(s)
responsible for the packaging operations:
(a) the date and time of the packaging operation
(b) the name of the responsible person carrying out the packaging operation and the
initials of the operators of significant steps
(c) a record to show that all packaging materials and labels have been assembled before
starting and checked for identity and conformity with the packaging instructions and
that the labels carry, or are to be printed with, the correct batch number and expiry date
(d) details of the packaging operations carried out, including references to equipment and
the packaging lines used
(e) notes on any special problems or unusual events, including details with signed
authorisation for any deviation from the master packaging instructions
(f) the signature of the person responsible for the operation confirming that the operation
has been carried out in accordance with the packaging and labelling instructions
(g) where practicable, a sample of the label used showing the added batch number and
expiry date and any other overprinting, as well as samples of any other pre-printed
packaging materials used
(h) the quantities and UINs/batch numbers of all printed packaging materials and bulk
product issued, used, destroyed or returned to stock and the quantities of obtained
product
(i) results for batch yield from the bulk supplied to be packed and, unless otherwise
justified, for reconciliation of labels and pre-printed packaging materials. Where
practicable, any part-batch packed should be subject to yield and reconciliation controls.
Where product is filled into unlabelled containers for later labelling, special precautions
should be taken to maintain the identity of the product during storage.
547 Batch records should show the name of the person responsible for releasing the product for
supply and confirm by way of that person’s signature that:
(a) all manufacturing documents have been reviewed
(b) all entries are complete
(c) there are no unexplained or unresolved deviations
(d) the product meets all specifications
(e) a final packed item has been visually examined.
548 Where finished product has been rejected, the batch records should include a note as to
the reason and should confirm that the batch has been status-labelled and appropriately
quarantined and/or disposed of.
549 Distribution records should be maintained for each batch of a product, in order to facilitate a
recall (see Chapter 11).
Computer records
551 Details of the records required where computer systems are used to store critical
manufacturing information or control manufacturing processes are described more fully in
Chapter 6.
Laboratory records
552 Details of the records required in quality control laboratories are described more fully in
Chapter 8.
Validation records
553 Records should be kept of all validation studies carried out. In addition to the raw data, the
records should include a technical report, set out in report format, providing details of the
rationale for the study, the methods used, when and by whom it was carried out, the results
and the conclusions.
Other
554 There should be written procedures and records of actions taken or conclusions reached,
where appropriate, for:
(a) pest control (including details of any pest control program implemented, records of
observations made as part of that program and any casual sightings, and details of any
corrective action taken)
(b) general maintenance, cleaning and sanitisation (cleaning and sanitising instructions
should include the name and strength of any cleaning/sanitising agent used)
(c) equipment installation and assembly, qualification and calibration (qualification and
calibration records should show tolerance limits)
(d) equipment maintenance, cleaning and sanitisation (cleaning and sanitising instructions
should include the name and strength of any cleaning/sanitising
agent used)
(e) personnel matters, including medical checks, training, clothing and hygiene
(f) environmental monitoring (including temperature and other controlled-environment
monitoring devices).
555 Clear operating procedures and, where appropriate, specific cleaning instructions, should be
available for major items of manufacturing and test equipment.
556 Log books or equivalent records should be kept for major or critical equipment, to record any
validations, calibrations, maintenance, or repair operations, including dates and the identity
of people who carried out those operations.
557 Log books or equivalent records should also record, in chronological order, the use and
cleaning of major or critical equipment and of the areas where the products have been
processed.
CHAPTER 6
Computer Systems
Manufacturing principles
• Where, in any step of manufacture, a computer is used for any activity that may affect the quality,
safety or efficacy of a product, then the computer system must be subject to quality system
management principles to ensure operational suitability.
• The introduction of computer systems into any manufacturing process, including materials
control, processing control, quality control and product distribution, must not adversely affect
product quality or quality assurance.
602 Before a system involving a computer is brought into use it should be thoroughly tested
and shown to be capable of achieving the intended outcomes. If a manual system is being
replaced by a computer system, or the computer system is being upgraded, both systems
should be run in parallel for a time as part of this testing and validation. The extent of
validation necessary will depend on a number of factors, including the intended outcomes,
whether it is prospective or retrospective and whether novel elements are incorporated.
603 If software has been commissioned specifically for the manufacturer, its development should
be documented at all stages and each step evaluated by expert review against the written
objectives. The stages to be documented include planning, specification, programming,
testing, installation and operational performance qualification.
604 If the software is ‘off-the-shelf’, but has been configured for the manufacturer’s use, then
installation qualification and operational qualification should be undertaken. This should
include a list of the values/fields/variables/parameters that have been chosen, with detail
of how this information is secured and made subject to change control and details of the
tests for security that were applied. The operational qualification will show how the system
successfully handles instructions and data.
605 If ‘off the shelf’ software has been partly or fully customised, its development should be
treated as in 603 above.
606 If the software is ‘off-the-shelf’ and has not been configured or customised for use, then
it should be precisely defined and an installation and performance qualification should be
carried out to demonstrate that user requirements have been satisfied.
607 Alterations to a computer system should be made only in accordance with a change control
procedure, which should include provision for checking and approving the changes and, to
the appropriate extent, performing operational and/or performance qualification.
608 When outside agencies provide a computer service, there should be a formal agreement
that includes a clear statement of the responsibilities of that outside agency.
609 A second authorised person should verify the entry of all critical data, such as master
formulae, into a computer system.
610 The system should be capable of providing printed copies of all stored data relevant to
product quality. Printed matter produced by computer peripherals should be clearly legible.
611 A procedure should be established to record and analyse errors and to enable corrective
action to be taken.
612 The system should record the identity of persons who enter or confirm critical data and
be capable of creating a time-stamped record of such entries or confirmations and of all
amendments.
613 Data should be entered only by authorised persons and there should be methods of
preventing unauthorised entry. There should be a defined procedure for the issue, alteration
or cancellation of authority to enter and amend data.
614 If the computer system is used for batch release, the authority to release should be clearly
defined.
615 Records should be backed up regularly and progressively and the backup retained at a
secure and remote location until the next backup is filed. Permanent archived electronic
records should be transferred to new media at regular intervals to avoid loss.
616 There should be contingency plans and recovery procedures for use in the event of a
breakdown of the system. This may be part of a broader disaster recovery plan.
CHAPTER 7
Production
Manufacturing principles
• Veterinary chemical products must be manufactured to specifications in accordance with
manufacturing information supplied as part of their application for registration including any
subsequent approved variations.
• Production operations must follow documented procedures that have been clearly defined by the
manufacturer.
• Any critical manufacturing process and any change to that manufacturing process, must be
validated and formally approved by an authorised person. Where a change in the manufacturing
process affects the registered specifications of the finished product, formal approval of such
changes must be obtained from the registering authority before the affected product is released
for supply.
Production guidelines
General
701 Each material used should be consistent with documented specifications and the master
manufacturing formula, and each step of manufacture carried out (such as receipt and
quarantine, quality assurance of raw materials, dispensing, processing, packaging, labelling
and quality control procedures) should be in accordance with documented procedures and
the master manufacturing instructions.
702 For each batch of product made, records should be kept of all materials used and of all
critical steps and control procedures carried out.
703 All surfaces which come into contact with raw materials, intermediate materials and
finished product should be maintained at an appropriate level of cleanliness at all stages of
manufacture.
704 The manufacturing process should be periodically monitored at all critical stages to ensure
both the reliability of the manufacturing process and product quality, including microbial
testing if relevant.
705 The identity and where relevant, the status of every material, including waste, should be
clearly shown on the outside of its container.
707 All incoming raw materials and packaging materials should be checked to ensure that the
consignment corresponds with the order. Containers should be cleaned where necessary
and clearly labelled.
708 Damage to containers and any other problem that might adversely affect the quality of a
material should be investigated, recorded and reported to Quality Control.
709 Incoming raw materials and finished products should be physically or administratively
quarantined immediately after receipt or processing until they have been released for use or
distribution. If physically quarantined, designated quarantine areas should be available for
this purpose.
710 Materials received as intermediate or bulk products should be handled on receipt as though
they were raw materials.
711 All materials and products should be stored under conditions that will minimise deterioration
and should be stored in an orderly fashion to permit batch segregation and stock rotation.
713 Each delivery of starting material should be given a unique identifying number (UIN). If one
delivery of material is made up of different batches, each batch should be considered as
separate for sampling, testing and release and be given a separate UIN.
714 Raw materials should be appropriately labelled on receipt with at least the following
information:
(a) the designated name of the starting material and the internal reference code
where applicable (each starting material should be identified by and used under one
name only)
(b) a number (UIN) given at receipt
(c) the status of the contents (e.g. quarantined, on test, released, rejected)
(d) where appropriate, an expiry date or a date beyond which retesting is necessary.
When computerised storage systems are used, all the above information need not
necessarily be specified in text on the label.
715 As soon as possible after receipt, each starting material should be assessed, in accordance
with a written procedure, for its suitability for use, as set out in Chapter 5.
716 A stock rotation system should be implemented to ensure that raw materials are used by
the nominated expiry/retest date.
717 There should be appropriate procedures or measures to ensure that the identity and
status of all containers of raw materials can be recognised from their labelling at all times.
Containers from which samples have been drawn should be identified.
718 The handling and treatment of animals used for production and testing purposes should
comply with all the relevant animal welfare guidelines. Animals used for production purposes
or for testing components, materials or products should, where appropriate, be quarantined
before use. They should be maintained and controlled and, where necessary, subjected to
testing to assure that they meet specifications and are suitable for the intended use. They
should be identified and adequate records maintained showing the history of their use.
720 Each delivery or batch of printed or primary packaging material received should be given a
specific reference number or identification mark.
721 Pre-printed labels must not be overprinted with a different name, dosage, formula or
strength of the product.
722 Labelling materials should only be issued for use by authorised personnel following an
approved and documented procedure.
723 Stocks of labels and pre-printed packaging materials should be checked annually and
outdated or obsolete material destroyed. This disposal should be recorded.
Cross-contamination control
724 Cross-contamination should be minimised by appropriate technical or organisational
measures, which may include:
(a) production in physically segregated areas (required for products such as live vaccines,
live bacterial preparations and some other biologicals, as well as penicillins and other
highly sensitising materials)
(b) adequately isolating plant and/or equipment by a suitable distance
(c) production on a campaign basis, followed by appropriate and validated cleaning, or
scheduling the manufacture of different products in an appropriate sequence
(d) providing effective air/dust extraction systems and/or airlocks
(e) keeping lids on mixing vessels
(f) avoiding recirculation or re-entry of untreated, or insufficiently treated, air
(g) keeping protective clothing inside areas where products with special risk of cross-
contamination are processed
(h) using effective and validated cleaning/decontamination procedures, and using cleaning
status labels
(i) using ‘closed’ production systems.
725 Where cross-contamination has the potential to cause a hazard to the treated animal, the
effectiveness of cross-contamination control measures should be monitored periodically
according to set procedures.
Process validation
726 Critical steps in the manufacture of each product or product group should be validated with
supporting data. The extent and method of validation/revalidation should be appropriate for
the manufacturing method and the type of product and its use.
727 When any new manufacturing formula, method of preparation or significant change is
adopted, steps should be taken to demonstrate its suitability for routine processing. The
defined process, using the materials and equipment specified, should be shown to yield a
product consistently of the required quality.
728 Validation studies should be conducted in accordance with defined procedures. They should
include the most challenging of any permitted ranges in process variables. Results and
conclusions should be recorded as technical reports.
Production procedure
Dispensing of raw materials
729 The raw materials used for a particular product must conform to the master manufacturing
formula. No substitution should be allowed unless the change is authorised in writing by an
authorised person.
730 Only raw materials that have been released for use and which are within their shelf life,
should be used.
731 Raw materials should be dispensed only by designated persons, following a written
procedure, in order to ensure that the correct materials are accurately weighed or measured
into clean and properly labelled containers.
732 The dispensing operation should be supervised or verified to the extent necessary to ensure
the accuracy of the weight/volume and the identity of the materials and all checks should
be recorded.
733 Materials dispensed for each batch should be kept together, isolated from other materials
and be conspicuously labelled with the product batch number.
Processing operations
734 Before any processing operation is started, steps should be taken to ensure that the work
area and equipment are clean, suitable for use and free from any raw materials, products,
product residues or documents not required for the current operation.
735 The product must be manufactured in full accordance with authorised batch manufacturing
instructions. Any variation from those instructions should be authorised in writing by an
authorised person.
736 Intermediate preparations, such as solutions used for pH adjustments or coating solutions,
should be prepared following the same system of master formulae and processing
instructions and their batch numbers should be carried forward onto the documents for the
finished products in which they are used.
737 Where operations on different products are carried out simultaneously or consecutively
in the same room, and where this is a product quality or safety issue, there should be
measures in place to prevent mix-up and/or cross-contamination.
738 At every stage of processing, products and materials should be protected from microbial and
other contamination.
739 When working with dry materials and products, precautions should be taken to minimise
the generation and dissemination of dust. This applies particularly to the handling of highly
active or sensitising materials.
740 At all times during processing, all materials, bulk containers, major items of equipment and,
where appropriate, rooms used, should be labelled or otherwise identified with the name of
the product or material being processed, its strength (where applicable) and batch number.
Where applicable, the label should also mention the stage of production.
741 Labels applied to containers, equipment or premises should be clear, legible, easily
understood and in the manufacturer’s agreed format. Colours may be used in association
with wording to indicate status.
742 Checks should be carried out to ensure that transfer lines and other pieces of equipment
used for the transportation of products from one area to another are clean before use and
are connected in a correct manner.
743 As far as possible, deviations from standard procedures should be avoided. Where
deviations occur, they should be approved in writing by an authorised person.
744 The production of incompatible products should be avoided in areas and equipment
destined for the production of veterinary chemical products, unless precautions are taken to
ensure the integrity of these veterinary chemical products.
745 All intermediate yields and the final product yield should be checked and quantities
reconciled against the theoretical or expected values by a competent person. Any
discrepancy that exceeds acceptable limits should be recorded on the batch records and
investigated, and the batch quarantined until its status has been determined.
747 Intermediate and bulk products should be stored under appropriate conditions that are
clearly defined and documented.
748 Material must be transported between premises or buildings in a manner that ensures that
the integrity and status of the material is maintained.
749 Delays in completion of the manufacturing process should be kept to a minimum. The
maximum holding time for intermediate and bulk materials should be clearly defined and
justified.
Process water
750 The quality of water required (potable or processed) should be specified and be consistent
with approved registration details.
751 Where water is treated for use as an ingredient, a specification for this process water should
be developed, based on sound physical, chemical and microbiological principles. Raw water
should be purified before use to meet this specification.
752 Where process water is used, a water quality manual should be prepared. This document
may be part of the manufacturer’s quality manual and should include:
(a) a drawing of the purification, storage and (where applicable) reticulation system,
showing all pipelines, valves, sample points, breather points, drain points, couplings,
instrumentation, pipe slopes, flow rates and velocities of water flow
(b) both a brief description of and a full specification for each element in the system,
including manufacturers’ recommended flow rates
(c) standard procedures for use, including start-up, shutdown, backwashing, regeneration,
sanitising and filter maintenance and testing
(d) a log of system changes, routine and non-routine maintenance (unless routine
maintenance is logged elsewhere and the log is readily available), investigations,
corrective action and validation studies
(e) chemical and microbiological specifications, including resample, action and
shutdown limits
(f) sampling instructions and testing procedures, including validation of procedures
(g) results of tests, including graphical presentations
(h) the positions of persons responsible for the operation and maintenance of the system
and their deputies
(i) periodic reviews, conducted at least once per year.
753 Process water should be tested at a frequency consistent with the history of successful
control. Sampling procedures should include ‘worst case’ sample points and production
conditions. The sample size tested should be sufficient to demonstrate process control.
754 Microorganisms recovered from total counts should occasionally be separately identified.
Atypical results should be investigated.
756 Before packaging operations are begun, a line clearance should be undertaken to ensure
that the work area, packaging lines, printing machines and other equipment are clean and
free from any products, materials or documents previously used, if these are not required for
the current operation.
757 The name and batch number of the product being handled should be displayed at each
packaging station or line.
758 All products and packaging materials to be used should be checked on delivery to the
packaging department for quantity, identity and conformity with the packaging instructions.
759 Containers should be clean before filling. Attention should be given to avoiding, and if
necessary removing, any contaminants such as glass fragments and metal particles.
760 Filling and sealing should be followed as quickly as possible by labelling. Where this is
not the case, appropriate procedures should be applied to ensure that no mix-ups or
mislabelling occur.
761 The correct printing of, for example code numbers or expiry dates, done either separately or
in the course of the packaging, should be checked and recorded. Printing by hand should be
re-checked at regular intervals.
762 Special care should be taken when using cut labels and when over-printing takes place
off-line.
763 Printed and embossed information on packaging materials should be distinct and resistant
to fading or erasing.
764 Checks should be made to ensure that any electronic code readers, label counters or similar
devices are operating correctly.
765 On-line control of the product during packaging should include checking at least the
following:
Samples taken away from the packaging line should not be returned.
766 Products that have been involved in an unusual event (e.g. a mid-process breakdown in
production or storage conditions) should only be reintroduced into the process after special
inspection, investigation and approval by authorised personnel. Detailed records should be
kept of this operation.
767 On completion of the packaging operation, yields should be determined and reconciliation
conducted. Acceptable limits should be established. Any significant or unusual discrepancy
should be investigated and satisfactorily accounted for before release.
768 Upon completion of a packaging operation, any unused batch-coded packaging materials
must be destroyed and the destruction recorded. Unused printed material should be
reinspected before being returned to stock.
770 All product batches must be sampled for quality control and must not be released for supply
until all specified tests are completed.
771 After release, finished products still under the control of the manufacturer, should be stored
under conditions consistent with the approved product label.
(a) limits on the age and total quality of residue that may be accumulated
(b) limits on the number of batches of residue that may be incorporated in a single batch
of product
(c) limits on the total quantity or proportion of residue that may be incorporated in a single
batch of product
(d) a procedure for use and/or disposal that will facilitate overall reconciliation
(e) any necessary testing or approval.
773 Rejected materials and products should be clearly marked as such and be stored separately
in clearly identified restricted (quarantine) areas. They should either be returned to the
suppliers or, where appropriate, reprocessed or destroyed. Action taken should be approved
and recorded by authorised personnel.
774 Recovery of all or part of earlier batches (that conform to the required quality), by
incorporation into a batch of the same product at a defined stage of manufacture, should
be authorised beforehand. This recovery should be carried out in accordance with a defined
procedure after evaluation of the risks involved, including any possible effect on shelf life.
The recovery should be recorded.
775 Finished product returned from the manufacturer’s own stores or warehouse
(e.g. because of soiled or damaged labels or outer packaging) may be relabelled, or
bulked for repacking, provided that there is no risk to product quality and the operation is
specifically authorised and documented. If such a product is relabelled, the operation should
be regarded as a formal packaging operation. If bulked, the operation should be regarded as
a formal processing operation.
776 Products returned from the market, which have left the control of the manufacturer, should
be destroyed, unless without doubt their quality is satisfactory. They may be considered for
re-sale, relabelling or recovery with a subsequent batch, only after they have been critically
assessed by Quality Control in accordance with a written procedure. The nature of the
product, any special storage conditions that it requires, its condition and history, and the
time elapsed since it was issued should all be taken into account in this assessment. There
should be no adverse effect on the shelf life of the product batch. Where any doubt arises
over the quality of the product, it should not be considered suitable for re-issue or re-use,
although basic chemical reprocessing to recover active ingredients may be possible. Any
action taken should be appropriately recorded.
777 The need for additional testing of any finished product that has been reprocessed, or into
which a recovered product has been incorporated, should be considered by Quality Control.
778 A suffix or batch number should be used to distinguish any bulked or relabelled material.
CHAPTER 8
Quality Control
Manufacturing principles
• Manufacturers of veterinary chemical products must have in place an effective quality control
system which is designed to ensure that before products are released from manufacture
for supply they meet specifications and have been manufactured in accordance with the
manufacturer’s documented procedures.
• The person responsible for quality control must be sufficiently independent of other aspects of
the manufacturing operation to allow effective implementation of the quality control function.
• Manufacturers must ensure that analytical laboratories and animal testing facilities used in a
step of manufacture follow the principles of good laboratory practice.
802 Where practicable, a quality control laboratory should be available and be adequately staffed
and equipped for the performance of all quality control tests required before, during and
after manufacture. Where there is no in-house facility, or the in-house facility does not have
the capability of doing all required quality tests, satisfactory alternative arrangements for the
required quality control testing should be made.
803 The principal duties of the head of Quality Control are summarised in Chapter 2
(Clause 210). Quality Control also has other duties, which may include:
(a) establishing adequate quality control specifications for all materials at all stages of
manufacture and for the finished product
(b) establishing, documenting, validating and implementing all quality control test
procedures
(c) assessing and releasing/rejecting starting and intermediate materials for each batch
(d) assessing and releasing/rejecting each batch of finished product for supply
(e) keeping reference/retention samples of materials and products
(f) ensuring the correct labelling of containers of materials and products
(g) monitoring the suitability of packaging materials
(h) monitoring the stability of the products, the suitability of expiry dates and product
storage conditions
(i) participating in the investigation of complaints related to the quality of the product
(j) monitoring environmental control of quality control laboratories and test animal houses
as appropriate
(k) reviewing trends in analytical results or yields
(l) establishing or approving procedures for animal quarantine, animal testing and the
recovery of biological material from animals for use in analysis, testing or production.
All these operations should be carried out in accordance with written procedures and
be recorded.
804 Analytical laboratories and animal testing facilities should follow the principles of good
laboratory practices (GLP). Written procedures should be established for at least the
following:
805 Quality Control personnel should have access to production areas for sampling and
investigation as appropriate. They should be empowered to take samples from any stage of
the manufacturing process or from finished products at any time, and should take and retain
samples, using documented procedures as required in Clauses 813–823).
806 Quality Control should receive prompt information on any proposed changes or modification
to material sourcing, specification, production procedures or written instructions.
(a) the records of this testing should indicate the source of the test results
(see Chapter 9)
(b) this laboratory should comply with AS ISO/IEC 17025, or with any subsequent
amendment
(c) this laboratory, if located in Australia, should be appropriately licensed by the APVMA to
test veterinary chemical products in the manner required.
808 Animals used for testing components and products should be handled in the same way as
those used in the manufacturing process (see Clause 718, Chapter 7).
Documentation
809 Laboratory documentation should follow the general principles given in Chapter 5
‘Documentation’. The following information should therefore be prepared by, or be readily
available to, Quality Control:
(a) specifications
(b) sampling procedures
(c) testing procedures and records (including analytical worksheets and/or laboratory
notebooks)
(d) analytical reports and/or certificates
(e) data from environmental monitoring, where required
(f) validation records of test methods, where applicable
(g) procedures for and records of, the calibration of instruments and maintenance of
equipment.
810 Any quality control documentation relating to a batch record should be retained for the
period defined in clauses 517–522, Chapter 5.
811 To facilitate compliance with the requirements of Clause 803, it is recommended that
records of analytical test results, yields and environmental controls be kept in a manner
permitting trend evaluation.
812 In addition to the information that is part of the batch record, other original data such as
laboratory notebooks and/or records should be retained and be readily available.
Sampling
Sampling plans
813 Sampling plans for starting materials (excluding packaging materials) should:
(a) * differentiate between certified, approved and other suppliers, including unknown
suppliers, as appropriate
(b) differentiate between starting materials that do not bear a manufacturer’s batch number
and those that do
(c) * take account of the nature of each material, for example its potency and whether
its place and method of manufacture may ensure against mix-up or even make mix-up
impossible
(d) take account of the intended use of the material (e.g. whether it is for injection)
(e) * differentiate between materials that may be expected to vary from container to
container (e.g. by separation or moisture uptake) and those that may not
(f) * prescribe the action to be taken where a delivery from a certified or approved supplier
has failed
(g) prescribe an increased sampling rate for damaged containers or for lots that do not
appear to be homogenous
(h) specify the extent of pooling of samples destined for tests other than identification
(i) require the sampling officer or analyst to initially examine each sample for homogeneity,
evidence of deterioration or other visible defect.
814 Sampling plans for packaging materials should take into account:
(a) the items shown as (*) listed in Clause 813 for starting materials
(b) the need to check the identity of each container or reel of labels and pre-printed
packaging materials
(c) the number of samples needed to reach a valid decision to approve or reject a delivery
in relation to quality-related defects.
Sampling Procedures
815 Samples should be taken in accordance with approved written procedures that describe:
816 The sampling procedure should be justified, taking into consideration the nature of the
material or the method of manufacture of the product being sampled.
817 Sample containers should bear a label indicating the contents, the batch number, the date
of sampling and the containers from which samples have been drawn.
818 All samples taken for quality control purposes should be taken by Quality Control personnel,
except samples for in-process control, which may be taken by authorised production staff.
819 All the in-process controls, including those made in the production area by production
personnel, should be performed according to methods approved by Quality Control and the
results should be recorded.
Retention samples
820 Quality Control should take and retain samples of:
821 Retention samples of materials and products should be of a size sufficient to permit at least
a full re-examination. In the case of active raw materials, the quantity taken
should be at least twice the quantity required to establish identity and purity. In the
case of finished products, the number of units retained will depend on the product and
should be adequate to permit re-examination at a suitable time and investigation of possible
complaints.
822 Retention samples from each batch of finished products should be retained for the period
specified in the Agvet Code Regulations (see Chapter 5 ‘Records’). Where practicable, these
samples should be kept in their final packaging. Where the finished product samples are
not stored in their final packaging, the packaging chosen should be of the same materials
as the manufactured product. Retention samples should be stored under the recommended
conditions.
823 Samples of starting materials (other than solvents, gases and water) should be retained for
at least two years after the release of the product, if their stability allows. This period may
be shortened if their shelf life, as mentioned in the relevant specification, is shorter.
Product release
824 Products should be released in accordance with the procedures specified in
Chapter 5.
CHAPTER 9
Contract Manufacture
Manufacturing principles
• Where all or part of the manufacture of a veterinary chemical product is contracted to another
party, the licensed manufacturer must ensure that before manufacture commences all parties
have signed a written ‘GMP Agreement’ that clearly specifies each party’s responsibility in
relation to every aspect of the manufacturing process, assurance of product quality and
consistency with product registration particulars.
• Arrangements for contracted steps of manufacture must not compromise the quality of
the product.
• Where a contractor is authorised to manufacture under the licence of another manufacturer,
the licence holder must exert direct control and oversight of the quality management of the
contracted step.
903 Contract manufacture may be undertaken only by a manufacturer who is the holder of an
APVMA Manufacturer’s Licence, unless the work undertaken by the contract acceptor falls
within the scope of the contract giver’s licence as specified in Agricultural and Veterinary
Chemicals Code Regulations 1995, cited below.
Regulation 59A A person who performs only a single step in the manufacture of a product is an
exempt person in relation to the manufacture if:
905 The Agreement should permit the contract giver, agreed third party or an APVMA-authorised
GMP auditor to visit the facilities of the contract acceptor for auditing purposes. The
agreement should require the contract giver to provide, for this purpose, access to details of
relevant analytical methodology and validation studies, or manufacturing procedures, quality
control tests and manufacturing records.
906 Technical aspects of the contract should be drawn up by competent persons with
knowledge of veterinary chemical manufacture, analysis and/or GMP, as is appropriate. All
arrangements for manufacture and analysis must be in accordance with the appropriate
product registration and be agreed to by both parties.
908 The contract giver should provide the contract acceptor with all the information necessary
to carry out the contracted operations correctly in accordance with registered particulars
and any other legal requirements. The contract giver should also ensure that the contract
acceptor is fully aware of any aspects of the product or the work which might pose a hazard
to the contract acceptor’s premises, equipment, personnel, or other materials or products
used or made on the premises.
(a) assessing the competence of the contract acceptor to successfully carry out the
required work
(b) ensuring that all arrangements for steps of manufacture, including any proposed
changes of a technical nature, are in accordance with the registration particulars for the
product concerned
(c) ensuring that all materials or processed products delivered to them by the contract
acceptor comply with their specifications, and that they have been released by a
competent authorised person.
911 The contract acceptor should refrain from any activity that may adversely affect the quality of
the product manufactured and/or analysed for the contract giver.
912 Where the contract acceptor is an analytical laboratory, the contract acceptor should make
available to the contract giver details of all analytical procedures carried out on the contract
giver’s materials, as well as details of any relevant validation studies carried out on those
procedures. Alternatively, where the contract acceptor considers an analytical method to be
confidential property, that method and its validation should be available to the APVMA.
913 The contract acceptor should make available to the contract giver details of all
manufacturing procedures and any quality control tests carried out on the contract giver’s
behalf, as well as copies of relevant manufacturing records.
914 The contract acceptor should not pass to a third party any of the work entrusted to them
under the contract without the prior evaluation and written consent of the contract giver.
915 Arrangements made between the contract acceptor and any third party should be subject to
a GMP Agreement between either the original contract giver or the contract acceptor and the
third party. Those arrangements should ensure that relevant manufacturing and analytical
information is made available to the third party in the same way as between the original
contract giver and contract acceptor. The third party must hold an APVMA Manufacturers
Licence, unless exempted under the Agricultural and Veterinary Chemicals Code Regulations
1995 or be otherwise authorised by the APVMA, as in the case of overseas manufacturers,
and accept the same responsibilities as the contract acceptor.
916 Manufacturing, analytical and distribution records, and retention samples should be kept
as specified in the GMP Agreement and in accordance with the Agricultural and Veterinary
Chemical Codes Regulations 1995 (see also Chapter 5 ‘Records’).
917 The contract acceptor should have adequate premises and equipment, knowledge and
experience, quality management system and competent personnel to satisfactorily carry out
the work ordered by the contract giver.
CHapter 10
Internal Audits
Manufacturing principle
• Manufacturers of veterinary chemical products must regularly and systematically carry out
internal audits of all aspects of their manufacturing operations, as well as of their quality
assurance program, in order to monitor compliance with their authorised procedures, standards
and requirements and ensure product quality. Steps must be taken to implement any necessary
corrective and preventive action identified by those internal audits and to assess the outcomes.
1002 Internal audits should be conducted by staff who have been trained and are competent in
internal audit procedures and should include, where practicable, staff who do not have direct
responsibility for the processes being audited. Alternatively, independent external auditors
may be used.
1003 Where the need for corrective action has been identified, steps should be taken to
address any observed deviations from the documented quality system and manufacturing
procedures. Corrective and preventive action should be monitored for effectiveness and
modified if necessary. Documented procedures should be amended if there is an identified
need to do so.
1004 Records should be kept of all internal audits undertaken, the outcomes of those audits,
details of any corrective and preventive action taken and the effectiveness of such action.
Chapter 11
Complaints AND
Product Recalls
Manufacturing principles
• Manufacturers of veterinary chemical products must have in place a system of handling
complaints regarding products they have manufactured or otherwise handled on the licensed
premises. There must be a documented system of recording, investigating and, where
appropriate, acting upon all complaints that may be related to product quality.
• Manufacturers must also have in place a documented and effective procedure for recalling from
the marketplace product that is known to be defective, or is suspected of being defective.
1102 There should be in place a documented procedure for receiving, recording, reviewing and,
where appropriate, acting upon all quality-related complaints received about veterinary
chemical products manufactured or handled on the premises. The procedure should include
the need to consider a recall in the event of a complaint concerning a possible product defect.
1103 Records should be kept of all complaints received, investigations carried out and their
outcomes and any corrective action taken to resolve the complaint and prevent the problem
happening again.
1104 All complaints related to product quality should be registered in a complaints register.
1105 Records should also be kept of all product returned for other reasons, the reason for the
return (e.g. out of date product), and its disposal. Records should be also kept of any
required corrective action.
1106 Responsibility for handling complaints related to product quality and for deciding the
measures to be taken should be delegated to a specified member or group of staff,
who should be given adequate resources to carry out the task. If this person is not the
person responsible for quality, the latter should be made aware of any such complaint or
investigation involving products manufactured or handled on the premises.
1107 The complaints procedure should incorporate the APVMA’s requirements for adverse
experience reporting.
1109 Complaints records should be reviewed regularly for any indication of specific or recurring
problems requiring attention and possibly the recall of products.
Recalls
1110 The APVMA should be notified if a manufacturer is considering recall action following
possibly faulty manufacture, product deterioration, or any other serious quality problem with
a product. The competent authorities of all countries to which defective products may have
been distributed should also be notified.
1111 There should be a written procedure for the initiation and management of any recall
activity, which should be aligned with the APVMA’s guidelines for the recall of agricultural
and veterinary chemical products and the requirements of the Trade Practices Act 1974.
Procedures should be regularly checked and updated when necessary.
1112 Responsibility for execution and co-ordination of recalls should be delegated to a specific
member or group of staff, who should be given adequate resources to handle all aspects of
the recalls with the appropriate degree of urgency. This responsible person should normally
be independent of the sales and marketing organisation. If this person is not the person
responsible for quality, the latter should be made aware of any recall operation.
1113 Recall operations should be capable of being initiated promptly and at any time, including
outside normal working hours. For that reason, the recalls co-ordinator should maintain a
regularly updated list of emergency contact numbers, including after-hours contact details.
1114 Distribution records should be readily available to the person(s) responsible for recalls, and
should contain sufficient information on directly supplied customers, including those for
exported products.
1115 Recalled products should be identified and stored separately in a secure area while awaiting
a decision on their fate.
1116 The progress of a recall should be recorded and a final report issued, including reconciliation
between the delivered and recovered quantities of products.
1117 Records should be kept of all recalls initiated (including internal ‘dummy runs’), all action
taken, as well as of details of all product returned as a result of recalls and its disposal.
Records should be in accordance with the APVMA’s guidelines for the recall of agricultural
and veterinary chemical products.
1118 The effectiveness of the recalls procedure should be evaluated from time to time by means
of internal ‘dummy runs’ and the procedure revised if necessary. The outcome of these
‘dummy runs’ should be recorded, together with details of any corrective action considered
necessary.
Note that these Annexes are intended to help with interpretation of this Code of GMP as it applies to
the particular type of product referred to. They are not meant to replace the core elements of the Code
and should be read in association with the relevant core elements.
Exempt persons or products are defined in Regulation 59 of the Agricultural and Veterinary Chemicals
Code Regulations 1995.
Annex 1—Manufacture of sterile products
ANNEX 1
Manufacture of sterile
products
Manufacturing principles
• Veterinary chemical products that are required to be, or are represented as being sterile, must
be manufactured:
– in separate, controlled areas in the premises that have
› high standards of hygiene
› a system of controlling particulate contaminants appropriate to the class of veterinary
chemical product being manufactured.
– with special care and attention to detail
– in accordance with procedures established and validated by the manufacturer.
• The manufacturer must establish procedures and have equipment available (or in the case of
bioburden, have access to equipment) to adequately monitor:
– the microbiological status of the environment in production areas
– the microbiological burden of the veterinary chemical products that are to be sterilised.
Introduction
Special precautions need to be taken when manufacturing sterile products in order to minimise
the risks of microbiological, particulate and pyrogen contamination. Protection of both the product
and the manufacturing environment is normally achieved through physical barriers, sanitation
procedures and rigorous staff training, as well as the supply of clean filtered air. While regulatory
audits frequently focus on cleanroom performance and validation, it needs to be appreciated
that contamination of product is often associated with random events rather than with airborne
contamination. Much depends on the skill, training and attitudes of the personnel involved. The
greater the risks involved, the more stringent the precautions that should be undertaken. Typically,
these stricter precautions include the use of ‘double barriers’ where processing and/or filling occurs
under a unidirectional airflow within a cleanroom environment. While terminal sterilisation may reduce
many of the risks, it will not eliminate them.
The requirements described in this Annex are divided into two sections: general guidelines that are
applicable to all manufacturers of sterile products, including those that involve terminal sterilisation,
and the more stringent guidelines that are associated with aseptic processing.
Periodic validation of key processes is necessary to demonstrate that such processes remain
effective. The sterility of the finished product is assured by validation of the sterilisation cycle in the
case of terminally sterilised products, and by ‘media-fill’ runs for aseptically processed products. It is
not sufficient that a finished product passes a prescribed sterility test. The sum of the manufacturing
precautions and the successful validation studies provides confidence in the quality of the product.
General
Premises
A1-001 Sterile products should be manufactured in areas that are designed and managed to
minimise microbial and particulate contamination.
A1-002 Wherever practicable, enclosed systems should be employed for product preparation
and filling.
A1-003 Sinks and floor drains should be excluded wherever possible. Where this is unavoidable, air
breaks should be fitted between the machine and sink or drain.
A1-004 Changing rooms should be designed as airlocks and provide physical separation of the
different stages of changing to minimise microbial and particulate contamination of
operators and protective clothing.
A1-005 Separate airlocks may be appropriate for moving some materials into controlled areas.
A1-006 An interlocking system or a visual and/or audible warning system should prevent the
opening of more than one airlock door at a time.
A1-007 Under all operational conditions, a filtered air supply to a particular area should maintain
both a positive pressure and a positive airflow relative to surrounding areas of a lower grade
and should flush the area effectively.
A1-008 A warning system should be provided to indicate failure in the air supply. Indicators of
pressure differences should be fitted between areas where these differences are important.
These pressure differences should be recorded regularly or otherwise documented.
Production areas
A1-009 Access to buildings must be restricted to authorised persons. Visitors to buildings should be
discouraged, kept to a minimum, and generally permitted only in areas not used for aseptic
operations. Visitors’ clothing must be in accordance with the area visited. All production
areas should, as far as possible, be designed to avoid the entry of non-operational
personnel.
A1-010 All exposed surfaces should be smooth, impervious and unbroken in order to minimise
the shedding or accumulation of particles or microorganisms and to permit the repeated
application of cleaning agents and, where used, disinfectants. Timber and laminate are
undesirable, as joints are hard to clean, timber is difficult to seal and laminate tends to lift,
chip and crack.
A1-011 To reduce accumulation of dust and to facilitate cleaning, there should be no uncleanable
recesses and a minimum of projecting ledges, shelves, cupboards and equipment. Doors
should be designed to avoid uncleanable recesses; sliding doors may be undesirable for
this reason.
A1-012 Pipes, ducts and other utilities should be installed so that they do not create recesses,
unsealed openings and surfaces that are difficult to clean.
A1-013 False ceilings should be sealed to prevent contamination from the space above them.
A1-014 Areas for the manufacture of terminally sterilised product must be designed to prevent the
mixing of sterilised and non-sterilised products.
A1-016 Items brought into sterile manufacturing areas, including means of transport, should be of a
standard of cleanliness compatible with the environmental standard for the area.
a) cleaning of bulk containers and their subsequent inspection for release for use in
processing
b) control of external contamination of bulk containers during use
c) assembly of filters and the connecting of hoses and pipelines
d) dismantling, cleaning and decontamination of pumps, filters, pipelines, and filling heads
and for their subsequent inspection for release for use in processing.
A1-018 Fumigation (with humidified formaldehyde vapour or other validated methods) may be used
to reduce microbial contamination in places inaccessible to surface disinfection. Fogging
(such as with peracetic acid) may also be acceptable if the process is validated.
A1-019 Disinfectants and detergents should be monitored for microbial contamination unless
pre-sterilised. Diluted disinfectants and detergents should be kept in previously cleaned
containers and should only be stored for defined periods unless they are also sterilised.
Environmental control
Air quality
A1-020 For the manufacture of sterile medicinal products, four grades of air quality are
distinguished, as follows:
Grade A: The local zone for high risk operations, e.g. filling zone, stopper bowls, open
ampoules and vials, aseptic connections. Normally such conditions are
provided by a unidirectional airflow workstation. Unidirectional airflow systems
should provide a homogeneous air velocity in the range of 0.36–0.54 m/s
(guidance value) at the working position in open cleanroom applications. The
maintenance of unidirectional airflow should be demonstrated. A unidirectional
airflow at lower velocities may be used in closed isolators and glove boxes.
Grade B: This is the background environment for a Grade A zone and is used for aseptic
preparation and filling.
Grade C/D: Clean areas for carrying out less critical stages in the manufacture of sterile
products.
A1-021 The classification of airborne particulate levels for Grades A–D is given in the following table.
Notes: (a) A discrete airborne particle counter is used to measure the concentration
of particles of sizes equal to or greater than the designated threshold.
Where consideration of particulate contamination is necessary to
ensure product quality, a continuous measurement system should be used
for monitoring the concentration of particles in the Grade A zone, and is
recommended for the surrounding Grade B areas. For routine testing, the
total sample volume should be not less than 1 m³ for Grade A and B areas
and preferably also in Grade C areas.
In order to reach the B, C and D air quality grades, the number of air changes
should be related to the size of the room and the equipment and personnel
present in the room. The air system should be provided with appropriate
terminal filters such as high efficiency particulate air (HEPA) filters for grades A,
B and C.
(b) The particulate conditions given in the table for the ‘at rest’ state should be
achieved after a short ‘clean up’ period of 15–20 minutes (guidance value) in
an unmanned state after completion of operations. The particulate conditions
for Grade A ‘in operation’ given in the table should be maintained in the zone
immediately surrounding the product whenever the product or open container is
exposed to the environment. It is accepted that it may not always be possible
to demonstrate conformity with particulate standards at the point of fill when
filling is in progress, due to the generation of particles or droplets from the
product itself.
(c) The guidance given for the maximum permitted number of particles in the ‘at
rest’ and ‘in operation’ conditions correspond approximately to the cleanliness
classes in the AS/NZS ISO 14644-1 at a particle size of 0.5 µm.
(d) These areas are expected to be completely free from particles of size greater
than 5 µm. As it is impossible to demonstrate the absence of particles with
any statistical significance, the limits are set to 1 particle/m3. During the
cleanroom qualification it should be shown that the areas can be maintained
within the defined limits.
(e) The requirements and limits will depend on the nature of the operations
carried out.
A1-022 Other characteristics such as temperature and relative humidity depend on the product and
the nature of the operations carried out, as well as on personnel comfort. These parameters
should not interfere with the defined cleanliness standard.
A1-023 Examples of operations to be carried out in the various air quality grades
A1-024 Operations preceding terminal sterilisation should normally be carried out in at least a
Grade D environment. Where there are increased risks of microbial contamination to the
product (e.g. filling of wide-necked containers, or where the product actively supports
microbial growth or must be held before sterilisation), preparation of solutions and
components should be carried out in at least a Grade C environment.
A1-025 A floor plan of the manufacturing areas should be available, showing the points of entry and
exit of air, classification of each room, number of air changes per hour and the differential
pressure(s).
A1-026 Where an isolator is used, the air classification required for the background environment
depends on the design of the isolator and its application. It should be controlled and for
aseptic processing be at least Grade D.
A1-027 Isolators should be introduced only after appropriate validation. Validation should take into
account all critical factors of isolator technology, for example the quality of the air inside and
outside (background) the isolator, sanitation of the isolator, the transfer process and isolator
integrity.
A1-028 Monitoring of isolators should be carried out routinely and include frequent leak testing of
the isolator and glove/sleeve system.
A1-029 Blow/fill/seal equipment used for aseptic production that is fitted with an effective
Grade A air shower may be installed in at least a Grade C environment, provided that Grade
A/B clothing (see clause A1-041) is used. The environment should comply with the viable
and non-viable limits ‘at rest’ and the viable limit only when in operation. Blow/fill/seal
equipment used for the production of products for terminal sterilisation should be installed
in at least a Grade D environment.
Environmental monitoring
A1-030 Cleanrooms and related areas should be monitored at planned intervals for airborne and
surface microbiological contamination and the results obtained used to determine ‘alert’
and ‘action’ levels. Monitoring should be frequent and should take place while normal
production operations are in progress. In the case of aseptic filling, it should provide
the basis for the assessment of aseptic hygiene throughout the filling process. Results
should be tabulated or graphed and assessed, and if necessary, prompt remedial action
taken according to the standards established. Additional testing should be carried out
to determine the effectiveness of such operations as cleaning and fumigation and the
influence of disruptions such as spillage or maintenance.
A1-031 Environmental monitoring of clean areas should include the following components:
A1-033 Microbiological and particulate contamination should be controlled and monitored for each
grade by a comprehensive procedure approved by quality management staff.
A1-034 Media used for environmental monitoring should be able to recover yeasts, moulds, fungi
and aerobic bacteria. Monitoring should include anaerobes where the type of product deems
this necessary. It is recommended to use two types of culture media (usually agars) for the
recovery of the above-mentioned organisms.
Personnel
A1-036 Management must delegate the supervision of the production process for sterile products
only to persons who are qualified by training and/or experience in the relevant aspects of
pharmaceutical/microbiological sciences. Where the person responsible for Quality is not
a qualified microbiologist, arrangements should be made to obtain regular external expert
microbiological advice.
A1-037 All personnel (including those concerned with cleaning and maintenance) should receive
training in procedures and in disciplines relevant to the correct manufacture of sterile
products, including hygiene (referred to in Chapter 2, Clauses 223–230) and the basic
elements of microbiology using expert microbiological advice. When external personnel
who have not received such training (e.g. building or maintenance contractors) need to be
brought in, particular care should be taken over their supervision.
A1-038 Personnel required to work in clean and aseptic areas should be selected with care to
ensure that they are not subject to any chronic disease or condition that would present an
abnormal microbiological hazard to the product. The same principle should be applied to
visitors to cleanrooms.
A1-039 Staff who have been engaged in animal handling, processing of animal tissues or products/
materials or culturing of microorganisms other than those used in the current manufacturing
process should not enter sterile-product areas unless rigorous and clearly defined entry
procedures have been followed. These entry procedures may include a period of quarantine
exclusion from the manufacturing area.
A1-040 Entry procedures, including changing and hand washing, should follow written instructions
designed to minimise contamination of clean area clothing or carry-through of contaminants
to clean areas.
A1-041 The minimum protective clothing requirements for each grade of controlled area are as
follows:
Grade A/B: Headgear should totally enclose hair and, where relevant, beard and
moustache; it should be tucked into the neck of the suit. A facemask should
be worn to prevent the shedding of droplets. Sterilised, non-powdered rubber
or plastic gloves and sterilised or disinfected footwear should be worn. Trouser-
legs should be tucked inside the footwear and garment sleeves into the gloves.
The protective clothing should shed virtually no fibres or particulate matter and
retain particles shed by the body.
Grade C: Hair and, where relevant, beard and moustache should be covered. Non-
powdered gloves should be worn. A single or two-piece trouser suit, gathered
at the wrists and with high neck and overshoes or dedicated shoes should be
worn. They should shed virtually no fibres or particulate matter.
Grade D: Hair and, where relevant, beard and moustache should be covered. A suitable
protective garment and overshoes or dedicated shoes should be worn. Gloves
(non-powdered) may be required.
Equipment
A1-042 Unidirectional airflow equipment must be regularly tested and the results recorded.
A1-043 Where necessary, equipment should be sterilised before use. The effect of the sterilisation
methods on the operation and durability of equipment should be considered. All sterilisation
procedures should be validated.
A1-044 Equipment used in the stages of processing of sterile products before sterilisation should
be designed and operated to minimise contamination by microorganisms and particulate
matter. As far as practicable, equipment, fittings and services should be designed and
installed so that maintenance and repairs may be carried out without personnel having
to enter the cleanroom. If sterilisation is required, it should be carried out after complete
reassembly wherever possible. Maintenance tools and equipment should be cleaned,
disinfected or sterilised before use.
A1-045 Vessels containing bulk sterile-filtered water or product should be vented through bacteria-
retaining filters.
A1-046 Autoclaves, gas sterilisers, sterilising ovens, and lyophilisers should be equipped with
automatic recorders that monitor the time and temperature and, where necessary, other
parameters of the sterilising cycle. This equipment should be qualified upon installation and
should be calibrated periodically. Records should permit verification of achievement of these
parameters with an appropriate degree of accuracy.
A1-047 A temperature-sensing probe for the automatic temperature recorder should be located at
the position in the steriliser shown by previous studies to be the coolest part of the loaded
chamber. Where sterilisers are fitted with a drain at the bottom of the chamber, it may also
be necessary to record the temperature at this position throughout the sterilisation period.
There should be regular leak tests on the chamber when a vacuum phase is part of the
cycle.
A1-048 Heat sterilisers should have provision for the entry of leads from temperature sensing
devices placed in product packs or simulated product packs during heat penetration studies.
A1-049 The pressure during steam sterilising cycles should be recorded at least manually.
A1-050 Steam used for sterilisation should not contain additives at a level that could cause
contamination of product or equipment. The use of ‘clean steam’ may need to be
considered.
A1-051 Where the quality of the product may be affected, air or any other gas admitted to an
autoclave, hot air steriliser or lyophiliser or used to promote positive pressure for filtration,
should be filtered through a bacteria-retaining filter. Compressed air used should also be
filtered through a bacteria-retaining filter.
A1-052 Water treatment plants and distribution systems should be designed, constructed and
maintained so as to ensure a reliable source of water of an appropriate quality. They should
not be operated beyond their designed capacity. Water should be produced, stored and
distributed in a manner that prevents microbial growth; for example, by constant circulation
at a temperature above 80 °C or at 4 °C or below.
A1-053 All water systems that supply processed water to be used in the manufacture of products
should be monitored for:
A1-055 Water used in the preparation of sterile products should comply with the relevant
pharmacopoeial standards or registration requirements. It may not need to be sterilised
before the product is manufactured.
A1-056 When distilled water is used in the final product, the time between distillation and the
final production should not exceed 24 hours unless provision is made for it to be held
at a temperature of at least 80 °C. A limit on the time that may elapse between solution
preparation and sterilisation should also be set.
Processing
A1-057 Containers or other materials liable to generate particles or fibres should not be taken into
areas supplied with Grade A, B or C air.
A1-058 The intervals between the washing, drying and sterilisation of components, containers and
equipment should be as short as possible and subject to a time limit appropriate to the
storage conditions. The interval between sterilisation and the use of these materials should
also be subject to a time limit.
A1-059 The time between the start of the preparation of a solution and its sterilisation should be
as short as possible and subject to a limit for each product that takes into account its
composition and the prescribed method of storage. Unless special storage conditions are
provided, bulk aqueous solutions should have no greater volume than can be used in one
working day and should be filled into final containers and sterilised within one working day.
A1-060 The microbiological load of products should be as low as practicable before sterilisation. It
should be monitored and an action level set that is related to the efficiency of the method
of sterilisation to be used, the risk of pyrogens and previous validation results. All solutions
and in particular, large volume infusion fluids should be passed through a filter of pore size
≤ 0.45 μm, where possible immediately before filling.
A1-061 Batch processing records for sterile products should include details of the sterilisation of
the batch, and where the batch is aseptically processed, details of the sterilisation of the
components and equipment used.
A1-062 The charts of automatic recorders of cycle parameters should constitute part of the batch
processing records of sterile products and should be marked to identify the batch or
batches to which each applies.
A1-063 Sterilisation records should be reviewed and approved as part of the batch release
procedure.
A1-064 Each separate sterilising basket, package, pallet etc. of products or components undergoing
sterilisation should be fastened, wired, sealed, lidded or otherwise secured to prevent mix-
up and should bear, in a conspicuous position, a visual indicator to demonstrate whether it
has passed through a sterilisation cycle.
A1-066 Preparations of microbiological origin should not be made or filled in areas used for the
processing of other medicinal products, unless justified by a written risk analysis.
A1-067 Components, containers and equipment should be handled after the final cleaning process
in such a way that they are not re-contaminated.
A1-068 Each procedure used for the sterilisation of a particular quantity or volume of a material
component or product should have been demonstrated by validation studies to be effective
and reliable. The validation should be verified at scheduled intervals based on performance
history, or when any significant change is made in the process or equipment.
A1-069 Where practicable, heat sterilisation is the method of choice. In any case, the sterilisation
process must be in accordance with product registration.
A1-070 Validated loading patterns should be established for all sterilisation processes.
A1-071 Biological indicators should be considered as an additional method for monitoring the
sterilisation process. They should be stored and used according to the manufacturer’s
instructions, and their quality checked by positive controls. If biological indicators are used,
strict precautions should be taken to avoid transferring microbial contamination from them.
Sterilisation by heat—general
A1-072 Each heat sterilisation cycle should be recorded on a time/temperature chart with a suitably
large scale or by other appropriate equipment with suitable accuracy and precision.
A1-073 Chemical or biological indicators may also be used, but must not take the place of physical
measurements.
A1-074 Sufficient time must be allowed for the whole of the load to reach the required temperature
before measurement of the sterilising time is commenced. This time must be determined
for each type of load to be processed. Typical loading diagrams should be part of the
standard operating procedures. Each sterilising load should contain one or more indicators
to show that the cycle has been completed.
A1-075 After the high-temperature phase of a heat sterilisation cycle, precautions should be taken
against contamination of a sterilised load during cooling. Any cooling fluid or gas in contact
with the product should be sterilised, unless it can be shown that any leaking container
would not be approved for use.
A1-077 The items to be sterilised should be wrapped in a material that allows removal of air and
penetration of steam but prevents recontamination after sterilisation. All parts of the load
should be in contact with the sterilising agent at the required temperature for the required
time.
Sterilisation by radiation
A1-079 During the sterilisation procedure the radiation dose should be measured. For this purpose,
dosimetry indicators that are independent of dose rate should be used, giving a quantitative
measurement of the dose received by the product itself. These dosimeters should be
inserted in the load in sufficient number, close enough together to ensure that there is
always a dosimeter in the irradiator. The position in the carrier receiving the lowest dose and
where appropriate, the highest dose should be represented. Where plastic dosimeters are
used, they should be used within the time limit of their calibration. Dosimeter absorbances
should be read soon after exposure to radiation.
A1-081 Validation procedures should ensure that the effects of variations in density of the packages
are considered.
A1-082 Materials handling procedures should prevent mix-up between irradiated and non-irradiated
materials. Radiation-sensitive colour indicators should also be used on each package to
differentiate between packages that have been subjected to irradiation and those that have
not.
A1-083 The total radiation dose should be administered within a predetermined time span.
A1-084 If an outside contractor carries out sterilisation by radiation, the contract giver is responsible
for ensuring that the requirements for this type of sterilisation are met and that the process
is validated. The responsibilities of the radiation plant operator (e.g. for using the correct
dose) should also be specified.
A1-087 Before exposure to the gas, materials should be brought into equilibrium with the humidity
and temperature required for the process. The time required for this should be balanced
against the opposing need to minimise the time before sterilisation.
A1-088 Each sterilisation cycle should be monitored with suitable biological indicators, using the
appropriate number of test pieces distributed throughout the load. The information so
obtained should form part of the batch record.
A1-089 For each sterilisation cycle, records should be made of the time taken to complete the cycle,
the pressure, temperature and humidity within the chamber during the process and the gas
concentration and the total amount of gas used. The pressure and temperature should be
recorded throughout the cycle on a chart. These records should form part of the
batch record.
Sterilisation by filtration
A1-090 Solutions or liquids should be filtered through a sterile filter of nominal pore size of
≤0.22 μm, or with at least equivalent microorganism-retaining properties, into a previously
sterilised container. Consideration should be given to complementing the filtration process
with heat or other treatment where the presence of filterable microorganisms is suspected.
A1-091 Positive pressure rather than negative pressure should be used in filtration processes.
To enhance the assurance of sterility, a second filtration step, immediately before filling, may
be advisable.
A1-093 The same filter should not be used for more than one working day, unless such use has
been validated.
A1-094 The filter should not affect the product by removal of ingredients from it or by release of
substances into it.
A1-095 The integrity of the sterilised filter should be verified immediately after use by an appropriate
method, such as a bubble point, diffusive flow or pressure hold test. Integrity testing before
and during use should also be considered. The time taken to filter a known volume of bulk
solution and the pressure difference to be used across the filter, should be determined
during validation and any significant variation from this during routine manufacturing from
this should be noted and investigated. Results of these checks should be included in the
batch record. The integrity of critical gas and air vent filters should be confirmed after use.
The integrity of other filters should be confirmed at appropriate intervals.
A1-097 Containers sealed under vacuum should be tested for maintenance of that vacuum after an
appropriate, pre-determined period.
A1-098 Filled containers of parenteral products should be inspected individually for extraneous
contamination or other defects. When inspection is visual, it should be done under suitable
and controlled conditions of illumination and background. Operators doing the inspection
should pass regular eyesight checks, with spectacles if worn, and be allowed frequent
breaks from inspection. Where other methods of inspection are used, the process should
be validated and the performance of the equipment checked at intervals. Results should be
recorded.
Quality control
A1-099 Where required or appropriate, tests for the following should be carried out on each batch of
product:
(a) sterility
(b) uniformity of contents
(c) potency
(d) pyrogenicity or endotoxin
(e) particulate matter.
For injectable and large volume infusion solution products, such testing is essential.
A1-101 Pharmacopoeial methods must be used for sterility tests. These methods should be
validated for the product(s) concerned.
A1-102 Where parametric release has been authorised, all calibrations and controls that were
specified in the application for authorisation must be rigorously maintained.
A1-103 Samples taken for sterility testing should be representative of the whole of the batch, but
should in particular include samples taken from parts of the batch considered to be most at
risk of contamination, for example:
(a) for products that have been filled aseptically, samples should include containers filled
at the beginning and end of the batch and after any significant intervention
(b) for products that have been heat sterilised in their final containers, consideration
should be given to taking samples from the potentially coolest part of the load.
(a) validation studies, including, in the case of aseptic filling, media fill results
(b) environmental monitoring results
(c) batch records including in-process test results
(d) equipment monitoring and performance records
(e) finished product test records.
Aseptic processing
Premises
A1-105 Aseptic filling should involve the minimum of human intervention.
A1-106 Sinks and drains should be excluded from aseptic filling/sealing rooms.
A1-107 Airlocks should be flushed effectively with filtered air. The final stage of the changing room
should, in the ‘at rest’ state, be the same grade as the area into which it leads. The use
of separate changing rooms for entering and leaving clean areas is sometimes desirable.
In general, hand-washing facilities should be provided only in the first (outer) stage of the
changing rooms.
A1-108 Adjacent rooms of different grades should have a pressure differential of 10–15 pascals
(guidance values). The air-flow pattern, location of equipment and movement of personnel
should afford protection of the zone of greatest risk (i.e. the immediate environment to
which a product and sterilised components that contact the product are exposed).
Production areas
A1-109 Products should be manufactured in a clean area up to the stage where they are sterilised,
and thereafter processed and filled into their final containers under aseptic conditions,
employing a double barrier system. The first barrier is provided by unidirectional flow
workstations in which the actual filling operations are carried out. The second barrier is
provided by the supply of filtered air into the room in which the operations are carried out. It
is desirable to maintain this room at a positive pressure relative to the outside environment.
A1-110 Non-sterile products should not be processed in the same area as sterile products.
A1-111 Grade B areas (see Clause A1-020) should be designed so that all operations can be
observed from the outside.
A1-113 Clean and, where necessary, sterile protective clothing must be supplied and worn in
production areas. Personnel working in associated areas not designated as clean or aseptic
areas should change into clean over-garments before entering the clean or aseptic areas
and remove these over-garments on exit. These outer garments should not be worn outside
the cleanroom suite.
A1-114 Clean over-garments should be made of such material and weave that they are comfortable
to wear, do not shed fibres, and restrict the passage of particulate matter. These garments
should not be fitted with pockets or cuffs.
A1-115 Disinfectants and detergents used in Grade A and B areas should be sterile before use.
Environmental control
A1-116 The ‘in operation’ and ‘at rest’ states should be defined for each cleanroom or suite of
cleanrooms.
A1-117 Examples of operations to be carried out in the various clean zone grades
Handling of sterile starting materials and components that are not to be filtered
Environmental monitoring
A1-118 Sampling methods used during operation should not interfere with zone protection. Results
from monitoring should be considered when reviewing batch documentation for finished
product release. Surfaces and personnel should be monitored after critical operations.
A1-119 Additional microbiological monitoring may be appropriate after activities such as major
maintenance, interruption to production and equipment validation.
Grade Air sample cfu/m3 Settle plates (diam. Contact plates Glove print
90 mm) cfu/4 hours(b) (diam. 55 mm) (5 fingers)
cfu/plate cfu/glove
B 10 5 5 5
C 100 50 25 -
D 200 100 50 -
(b) Individual settle plates may be exposed for less than four hours, but should not
be exposed for more than four hours unless validated. Additional plates may
be used at a single location to sum to four hours exposure. The results from
settle plates should not be interpreted as equivalent to those from volumetric
sampling. cfu = colony forming units
A1-121 It should be demonstrated that airborne cleanliness classifications are met during
operations. Appropriate alert and action limits should be set for the results of particulate
monitoring. Operating procedures should prescribe corrective action, if these limits are
exceeded.
Personnel
A1-122 Only the minimum number of personnel essential for production and in-process control
operations may be allowed in aseptic or clean areas; this is particularly important during
aseptic processing. Inspections and controls should be conducted outside the clean areas
as far as possible.
A1-123 Personnel engaged in servicing equipment or other non-routine activities must observe the
same precautions and hygiene standards as production personnel.
A1-124 Wristwatches, make-up and jewellery should not be worn in clean areas.
A1-125 Outdoor clothing should not be brought into changing rooms leading to Grade B and C
rooms. Clean sterile (sterilised or adequately sanitised) protective garments should be
provided at each work session for every worker in a Grade A/B area. Gloves should be
regularly disinfected during operations. Masks and gloves should be changed at least at
every working session.
A1-126 Clean area clothing should be cleaned and handled in such a way that it does not gather
additional contaminants that can later be shed. These operations should follow written
procedures. Separate laundry facilities for such clothing are desirable.
Equipment
A1-127 A conveyor belt should not pass through a partition between a Grade A or B area and a
processing area of lower air cleanliness, unless the belt itself is continually sterilised (e.g. in
a sterilising tunnel).
Processing
A1-128 Activities in clean areas, especially when aseptic operations are in progress, should be kept
to a minimum and movement of personnel should be controlled and methodical to avoid
excessive shedding of particles and organisms as a result of over-vigorous activity. The
ambient temperature and humidity should be set to provide a comfortable environment,
taking into account the nature of the garments worn.
A1-129 Components, containers, equipment and any other article required in a clean area where
aseptic work takes place should be sterilised and passed into the area through double-
ended sterilisers sealed into the wall, or by a procedure that achieves the same objective
of not introducing contamination. Noncombustible gases should be passed through
microorganism-retentive filters.
A1-130 Validation of aseptic processing should include a process simulation test using a nutrient
medium (media fill). The process simulation test should imitate as closely as possible the
routine aseptic manufacturing process, including predictable interventions and worst-case
situations. Process simulation tests should be performed as initial validation with three
consecutive satisfactory simulation tests per shift and be repeated at defined intervals (not
less than once annually) and after any significant modification to the heating, ventilation
and air conditioning (HVAC) system, equipment, process or number of shifts. The number
of containers used for media fills should be sufficient to enable a valid evaluation. For
small batches, the number of containers for media fills should at least equal the size of
the product batch. The target should be zero growth, but production need not be halted if a
contamination rate of less than 0.1% is observed.
The manufacturer should establish alert and action limits.
A1-131 Care should be taken that any validation does not compromise the processes.
ANNEX 2
IMMUNOBIOLOGICALS AND OTHER
PRODUCTS OF BIOLOGICAL ORIGIN
Manufacturing principles
• Veterinary immunobiological products and other chemical products of biological origin including
those that are manufactured using a specified biological process must be manufactured:
– using only biological starting materials that are, or are derived from biological materials
demonstrated to be as free as practicable from adventitious contamination
– in premises designed, constructed and maintained so as to provide an appropriate level of
containment of the biological or microbiological agents being handled and to permit effective
decontamination from these agents or from toxic residues by procedures that:
› are established and validated by the manufacturer
› maintain the safety of personnel.
– in cases where uniformity of product depends on deriving batches from a seed lot
› by maintaining the lots in secure and protective storage
› by keeping meticulous records of their origin and disposition.
Essential information
The manufacture of veterinary immunobiological and other biological products is frequently complex
and the role of the quality assurance system is of the utmost importance. Due to nature of biologics
manufacture (e.g. cultivation of microorganisms), the products must be well protected against
contamination and cross-contamination. This Annex should therefore be read in conjunction with
Annex 1.
Premises
General
A2-001 Documentation relating to the premises should be readily available. The manufacturing
site and buildings should be described in sufficient detail (by means of plans and written
explanations) so that the designation and conditions of use of all the rooms are correctly
identified, as well as the biological agents that are handled in them. The flow of people and
product should also be clearly marked.
A2-002 Animal species accommodated in the animal houses or otherwise on the site should be
identified on the site plans or accompanying notes.
A2-003 Activities carried out in the vicinity of the site should also be indicated on the site plans
or accompanying notes. Plans of clean or contained areas should describe the ventilation
system, indicating inlets and outlets, filters and their specifications, the number of
air changes per hour and pressure differentials. They should indicate which pressure
differentials are monitored by pressure indicators.
A2-005 Live biological agents should be handled in contained areas that may also be clean areas.
The level of containment should depend on the pathogenicity of the microorganism and
whether it has been classified as exotic.
A2-006 Inactivated biological agents should be handled in clean areas. Clean areas should also be
used when handling non-infected cells isolated from multi-cellular organisms and filtration-
sterilised media.
A2-007 Open circuit operations involving non-viable products or components not subsequently
sterilised should be carried out within a unidirectional Grade A airflow workstation in a
Grade B area.
A2-008 Other operations where live biological agents are handled, such as quality control, research
and diagnostic services, should be contained and separated if production operations are
carried out in the same building. The movement of personnel and the level of containment
should depend on the pathogenicity and origin of the biological agents. Where there is the
risk of introducing highly pathogenic or exotic organisms (e.g. via quality control activities),
the level of containment should be adequate to cope with all such risks. Containment may
also be required if quality control or other activities are carried out in buildings in close
proximity to those used for production.
(e) They should have changing rooms designed and used as air locks and equipped with
washing and showering facilities as appropriate. Air pressure differentials should be
such that there is no flow of air between the work area and the external environment or
risk of contamination of outer clothing worn outside the area.
(f) An air lock system for the passage of equipment should be constructed so that there
is no flow of contaminated air between the work area and the external environment, or
risk of contamination of equipment within the lock. The air lock should be of a size that
enables the effective surface decontamination of materials being passed through it.
Consideration should be given to having a timing device on the door interlock to allow
sufficient time for the decontamination process to be effective.
(g) There should be a barrier double-door autoclave for the secure removal of waste
materials and introduction of sterile items, where appropriate.
A2-010 Transfer hatches and changing rooms should have an interlock mechanism or other
appropriate system to prevent the opening of more than one door at a time. Changing rooms
should be supplied with air filtered to the same standard as that for the work area, and
be exhausted to produce an adequate air circulation independent of that of the work area.
Transfer hatches should normally be ventilated in the same way, but unventilated hatches, or
those equipped with supply air only, may be acceptable.
A2-011 With the exception of blending and subsequent filling operations, only one biological
agent at a time should be handled within an area. Production operations such as cell
maintenance, media preparation, or virus culture likely to cause contamination should not
be performed in the same area at the same time. Where the same room is used for more
than one purpose, effective decontamination and line clearance between operations should
be in place.
A2-013 Killed vaccines should be blended, filled, and sealed under aseptic conditions and
segregated from the processing areas where culturing is carried out.
A2-014 The filling of containers with live vaccines, including those prepared from attenuated strains,
must be appropriately separated from other aseptic filling operations. This may be achieved
by using separate areas or by elapsed time and effective decontamination procedures.
A2-016 Production areas must be thoroughly cleaned and disinfected after any non-sterile operation,
such as maintenance and before aseptic processing resumes.
Personnel
A2-017 In the case of biological agents known to cause disease in humans, adequate measures
should be taken to prevent infection of personnel working with live organisms or with
animals. Where relevant, the personnel should be appropriately vaccinated and subject to
regular medical examination.
A2-018 Adequate measures should be taken to prevent biological agents being carried outside
the manufacturing plant by personnel. Dependent on the type of biological agent, such
measures may include complete changing of clothes and compulsory showering before
leaving the production area.
A2-020 Only personnel essential for production and in-process control operations, maintenance and
cleaning should be allowed into processing areas.
A2-021 Personnel working in areas designated as ‘clean/aseptic’ or ‘culturing’ should change into
clean over-garments before moving from one area to another, and the over-garments must
be removed on exit from the relevant area. The same principles should apply when staff
move from other areas into clean/aseptic or culturing areas.
Equipment
A2-022 Any closed equipment used for the primary containment of biological agents should be
designed and constructed to prevent any leakage or the formation of droplets and aerosols.
Inlets and outlets for gases should be protected to achieve adequate containment (e.g. by
the use of sterilising hydrophobic filters). The introduction or removal of material should take
place using a sterilisable closed system, or possibly in an appropriate unidirectional air flow.
A2-023 Separate incubators should be used for infected and non-infected containers and also
generally for different organisms or cells. Incubators containing more that one organism
or cell type will only be acceptable if adequate measures are in place to seal, surface
decontaminate and segregate the containers. All containers should be individually labelled.
Equipment used for the storage of biological agents or products should be designed and
used in such a manner as to prevent any possible mix-up. All stored items should be clearly
and unambiguously labelled and be in leak-proof containers. Items such as seed stock (cell
or organism) should be stored in dedicated equipment.
A2-024 The process of loading freeze-driers requires an appropriate clean or contained area.
Unloading freeze-driers potentially contaminates the immediate environment. Therefore,
for single-ended freeze-driers, the cleanroom should be decontaminated at the end of the
process and before a further manufacturing batch is introduced into the area, unless this
contains the same organisms. Double-door freeze-driers should be sterilised after each
cycle unless opened in a clean area. Sterilisation of freeze-driers should be done at least
after each campaign.
A2-026 In heat sterilising processes, it is essential that the whole load reaches the sterilisation
temperature. Account must be taken of heat-up times for various loads and ‘typical loading’
diagrams should be part of standard operating procedures. Standard operating procedures
must be available.
A2-027 Items to be sterilised by autoclaving must be wrapped in a material that allows the removal
of air (either by free steam or evacuation of the chamber) and its replacement by steam, but
does not permit recontamination when dry.
A2-028 Sterilisation by filtration should not be used when sterilisation by heat is acceptable.
Positive pressure rather than negative pressure should be used in filtration processes. The
integrity of the filter system must be tested immediately after each use.
A2-029 When re-useable filters are used, they should be effectively cleaned and sterilised after each
use. Consideration should be given to using individual filters for one type of
solution only.
A2-030 Unidirectional airflow equipment should be regularly tested and the results recorded.
Cleanrooms and related areas should be monitored at planned intervals for
microbiological contamination.
A2-032 Animals, biological agents and tests carried out should be identified in such a way as to
prevent any risk of confusion and to control all foreseeable hazards.
A2-033 Animal testing facilities should be sufficiently secure to ensure that unauthorised entry is
prevented and that animals cannot break in or escape. This applies particularly to facilities
where live challenge tests are being carried out. Procedures should be in place to ensure
that animals cannot be incorrectly identified or otherwise mixed up by staff. Attention should
be also be given to decontamination and environmental requirements, where applicable.
A2-034 Animal houses accommodating animals used for, or intended to be used for, production
purposes should be provided with appropriate containment and/or clean area measures and
should be separated from other animal accommodation.
A2-035 Animal houses accommodating animals that are used for quality control purposes that
involve pathogenic biological agents should be adequately contained.
Production
General
A2-036 Production of biological agents may take place in either clean or controlled areas, provided
it is carried out in totally enclosed and heat sterilised equipment, with all connections being
also heat sterilised after making and before breaking. It may be acceptable for connections
to be made under local unidirectional airflow, provided these are few in number and proper
aseptic techniques are used and there is no risk of leakage. The sterilisation parameters
used before breaking the connections must be validated for the organisms being used.
Different products may be placed in different bioreactors within the same area, provided that
there is no risk of accidental cross-contamination. However, organisms generally subject to
special requirements for containment should be in areas dedicated to such products.
A2-037 Critical procedures, including methods for sterilisation, disinfection, virus removal and
inactivation, should be validated and subject to monitoring and in-process controls.
A2-038 Substances of animal origin should be prepared from homogeneous bulk material,
designated with a batch number. A batch may contain material derived from as many
animals as is desired, but once designated and given a batch number, a batch should not be
added to or contaminated in any way.
Starting materials
A2-039 Written specifications for starting materials should, where appropriate, include details of the
supplier, the method of manufacture, the geographical origin and the animal species from
which the materials are derived. The controls to be applied to starting materials must be
included. Microbiological controls are particularly important.
A2-040 The results of tests on starting materials must comply with the specifications. Where the
tests take a long time, it may be necessary to process starting materials before the results
of analytical controls are available. In such cases, the release of a finished product must be
conditional upon satisfactory results of the tests on starting materials.
A2-041 Where substances of animal origin (e.g trypsin and serum albumin) are used as ingredients
of culture media, during processing or as added constituents of vaccines or diluents,
batch records should allow traceability and confirmation with registered specifications and
quarantine requirements for all such substances.
Media
A2-042 Media used in fermenters or bioreactors should preferably be sterilised in situ or in line.
Heat is the preferred method. Gases, media, acids, alkalis, defoaming agents and other
materials introduced into sterile bioreactors should themselves be sterile.
A2-043 Where heat-labile media components are required, these should be sterilised by other
acceptable means (e.g filtration, gamma irradiation) and added aseptically to the heat-
sterilised base medium.
A2-045 The origin, history since receipt, preparation, form and storage conditions of seed material
should be described in full. The number of generations (doublings, passages) between the
master seed lot or cell bank and the finished product should be defined and be consistent
with the product registration. Seed lots and cell banks should be adequately characterised
and tested for contaminants. Acceptance criteria for new seed lots and cell banks should be
established.
A2-046 During the establishment of a seed lot or cell bank, no other living or infectious material
should be handled at the same time in the same area or by the same person. Seed lots and
cell banks should be established, stored and used in such a way as to minimise the risks of
misidentification, contamination or any alteration.
A2-047 Evidence of the stability and recovery of the seeds and cell banks should be generated and
recorded. Storage containers should be secure, clearly labelled and held at an appropriate
temperature. Storage conditions should be properly monitored. An inventory of each seed lot
and cell bank should be maintained and each container accounted for.
A2-048 Only authorised personnel should be allowed to issue and handle seed material.
Operating techniques
A2-049 The formation of droplets and the production of foam should be avoided or minimised during
manufacturing processes. Centrifugation and blending procedures that may lead to droplet
formation should be carried out in appropriate clean or contained areas to prevent transfer
of live organisms.
A2-050 There should be documented procedures for the prompt handling of spillages of live
organisms. Validated decontamination measures should be available for each organism.
Where different strains of a single species of bacteria or very similar viruses are involved,
the process need be validated against only one of them, unless there is reason to believe
that they may vary significantly in their resistance to the agent(s) involved.
A2-051 Operations involving the transfer of materials such as sterile media, cultures or product
should be carried out in pre-sterilised closed systems wherever possible. Where this is
not possible, transfer operations must be protected by unidirectional airflow workstations.
Checks should be made to ensure that vessels are correctly connected when addition of
cultures takes place.
A2- 052 After connection, before the flow of product, and again before disconnection fermenter
sampling, addition ports and connectors should be sterilised with steam. However, in
some circumstances, chemical disinfection of ports and unidirectional air flow protection of
connections may be acceptable.
A2-053 Equipment, glassware, the external surfaces of product containers and other such materials
should be disinfected using a validated method before transfer from a clean or contained
area. Only the absolute minimum of batch documentation required should enter and leave
the area. If obviously contaminated, such as by spills or aerosols, or if the organism involved
is an exotic, the paperwork must be adequately disinfected through an equipment transfer
hatch, or the information transferred out by alternate means.
A2-054 Liquid or solid wastes should be sterilised or disinfected before transfer from a clean or
contained area. However, alternative transfer procedures may be appropriate in some cases.
A2-055 Articles and materials, including documentation, entering a production room should be
carefully controlled to ensure that only materials concerned with production are introduced.
A2-056 All materials entering a clean or contained area should be sterilised. Where practicable,
heat-stable articles and materials entering a clean or contained area should do so through
a double-ended autoclave or oven. Sterilisation of articles and materials elsewhere is
acceptable, provided they enter through an airlock and appropriate precautions are taken
(e.g double wrapping, surface disinfection).
A2-057 Precautions should be taken to avoid contamination or confusion during incubation. There
should be a cleaning and disinfection procedure for incubators.
A2-058 With the exception of blending and subsequent filling operations, or when totally enclosed
systems are used, only one live biological agent should be handled within a production room
at any given time. Production rooms must be effectively disinfected between the handling of
different live biological agents.
A2-059 Addition of inactivating agent to the bulk material should be immediately followed by
stirring or mixing to ensure even distribution of the agent. The bulk material should then be
transferred to a sterile inactivation vessel to ensure all of the bulk material is exposed to
the inactivating agent.
A2-060 Vessels containing inactivated product should not be opened or sampled in areas containing
live biological agents. All subsequent processing of inactivated products should take place
in Grade A/B clean areas or enclosed equipment dedicated to inactivated products.
A2-061 Containers of bulk material should be sealed, appropriately labelled and stored under
specified conditions.
A2-062 There should be a system to assure the integrity of all containers and their closures after
filling. This requirement applies to containers of bulk materials, intermediates and finished
products.
A2-063 The capping of vials containing live biological agents should be performed in such away
that contamination of other products, or escape of the live agents into other areas or the
external environment, does not occur.
A2-064 When there is a delay between the filling of final containers and their labelling and
packaging, procedures should be specified for the storage of unlabelled containers so as to
preserve product identity and to ensure satisfactory storage conditions.
Quality control
A2-065 In-process controls that are crucial to product quality, but which cannot be carried out on the
finished product, should be performed at an appropriate stage of production.
A2-066 Where testing of bulk or intermediate materials is required, a sufficient quantity of sample
should be retained, under appropriate storage conditions, to allow repetition or confirmation
of the test result if necessary.
A2-067 Where production of a biological product involves continuous culture, the quality control
requirements arising from such a production method should be appropriately addressed.
A2-068 Sufficient quality control testing should be undertaken to ensure that the product complies
with the approved registration particulars.
A2-069 Quality Control should maintain cumulative records of environmental control, the testing of
manufacturing equipment and all other quality control tests where applicable, and should
take into account the results of such testing before releasing any batch of product for
distribution.
ANNEX 3
Non-sterile therapeutic
products (other than
ectoparasiticides, premixes,
supplements AND biological
feed additives)
Introduction
Additional guidance is required for some product types because of the wide range of non-sterile
veterinary products subject to licensing and differences in consumer expectations relating to product
quality. These products are often manufactured in facilities that are also used to make
non-veterinary chemical products. This may pose additional risks for cross-contamination that need to
be addressed.
Electrolytes
The term ‘electrolytes’ normally refers to solutions of mineral supplements that have various
applications. ‘Electrolytes’, sometimes with vitamins and other medications added, may be used
to treat serious dehydration associated with diarrhoea and other ailments. Such products can be
administered either by injection, in which case they are required to be sterile (see Annex 1), or orally,
in which case they are required to comply with any additional relevant requirements of this Annex.
In the racing industry, ‘electrolyte’ products are commonly used to treat dehydrated animals following
racing. The products are usually added to drinking water or to feed after the race. Other ‘electrolyte’
products are simply vitamin and mineral supplements that are added to feed and water on a regular
basis. In some cases, the products are manufactured in dry powder form. Such products are treated
as vitamin and mineral supplements for GMP purposes (see Appendix 6).
Bloat oils
This type of product usually consists of a mineral (petroleum) oil mixed with a detergent. It is
administered to individual animals by drenching or painting it on the animal’s flank, or sprayed onto
pasture or added to water in drinking troughs. These products are registered veterinary chemicals
and consequently need to be manufactured in compliance with the manufacturing principles and the
core elements of this GMP Code, taking into account the nature and use of the product. Where the
product is manufactured in a petroleum refinery, only the relevant aspects of GMP need to be applied.
Production
A3-002 The chemical and microbiological quality of water used for production should be specified
and monitored.
A3-003 Mixing and filling processes should ensure homogeneity. Procedures should be in place to
ensure that homogeneity is maintained during filling and after stoppages.
A3-004 When the finished product is not packaged immediately after processing, the maximum
period of storage and the storage conditions should be specified and respected.
ANNEX 4
Herbal products
Introduction
Control of starting materials, storage and processing assume particular importance in the
manufacture of herbal medicinal products because of their often complex and variable nature, and
the number and small dosage of defined active ingredients.
Premises
Storage areas
A4-001 Some plants, extracts, tinctures and other preparations may require special conditions
of humidity, temperature or light protection. These conditions should be provided and
monitored.
Documentation
Specifications for starting materials
A4-002 Apart from the requirements described in the core elements of this GMP Code (see Chapter
5), specifications for medicinal crude plants should include, as far as possible:
(a) the full botanical name (including, if appropriate, the name of the originator of the
classification, e.g. Linnaeus)
(b) the preferred source of the plant (country or region of origin and, where applicable,
method of cultivation, time of harvesting, collection procedure, pesticides that
can/cannot be used etc.)
(c) plant description, including macroscopic and microscopic details, where a whole plant
is sourced; an authentic reference specimen should be available for identification
purposes
(d) the part of the plant required (i.e. whether the whole plant or only a specific part such
as the roots, leaves, whole tops etc.)
(e) the method used for drying
(f) a physical description of the material
(g) suitable identification tests, including, where appropriate, tests for known active
ingredients, or markers, and the limits accepted
(h) acceptable levels of possible chemical or biological contamination (pesticide, fungicide,
herbicide, fungal and/or microbial, including aflatoxins, pest infestations, toxic metals,
and other possible contaminants and adulterants), as well as the methods used to
determine such contamination
(i) tests for foreign materials.
A4-003 Any treatment used to reduce fungal/microbial contamination or other infestation should
be documented. Specifications for such procedures should be available and should include
details of processes, tests and limits for residues.
ANNEX 5
Ectoparasiticides
Introduction
Ectoparasiticides are those products applied externally to animals to control only external parasites.
Ectoparasiticides differ from most other veterinary chemical products in that they contain pesticides
that may be toxic and generally incompatible with other forms of medicinal products. Consequently,
ectoparasiticides should not be manufactured in the same area as other veterinary chemical
products unless special precautions are taken to prevent cross-contamination. These precautions
might include the use of dedicated equipment that is adequately separated from other processing
areas or, where the same equipment is to be used for incompatible products, the use of scheduling
and validated cleaning procedures.
Because some of the active materials are also used for agricultural chemicals, ectoparasiticides are
occasionally manufactured in plants that also make agricultural chemicals. In those circumstances,
rigorous precautions need to be taken to eliminate the risk of cross-contamination with pesticides,
herbicides and incompatible materials.
Some of the products such as sheep dips, are made in large volumes using solvents and other
materials that are sometimes stored in drums or specially constructed storage vessels. Outdoor
storage of such materials may be acceptable, provided storage conditions such as temperature are
appropriate for the materials involved.
Safety issues, such as the explosion hazard of excessive dust generation and the possibility of
inhalation of chemical laden dust by personnel (e.g. organophosphate pesticides), should be
considered in the design and location of ectoparasiticide manufacture.
Attention is drawn to the need to comply with dangerous goods and hazardous substances legislation
that may require special storage condition for goods that are of a dangerous or hazardous nature.
A5-002 Similarly, where ectoparasiticides are manufactured in a facility that also manufactures
agricultural chemicals, they should be made in a separate area of the plant, using
equipment dedicated to veterinary chemical manufacture. Special measures are needed to
prevent cross-contamination with agricultural chemicals, particularly where shared facilities,
such as packing rooms, are used.
A5-003 Bunding may be required in some situations to meet the requirements of dangerous goods
and environment protection legislation.
A5-004 Outside storage of high volume materials (e.g. solvents in 200 litre drums) may be
acceptable, provided they are in adequately sealed containers and outside storage
conditions are unlikely to adversely affect their quality.
Manufacture
A5-005 Manufacturing processes that involve the application of a liquid premix onto an inert
carrier powder should ensure adequate dispersion of the liquid and, therefore, the active
ingredient(s). Mixing times and methods should ensure batch homogeneity.
A5-006 Measures should be in place to prevent cross-contamination from hoses, fixed pipework and
connections.
ANNEX 6
Premixes, supplements AND
biological feed additives
Introduction
This Annex covers a range of products that are generally thought of as nutritional products, that
are purported to have a therapeutic benefit and are therefore required to be registered. As a
consequence, they must be manufactured in compliance with GMP standards. In most cases they
are administered to animals in their feed or drinking water, which means that individual dosage is not
controllable. The range of products includes:
• premixes
• supplements
• mined mineral supplements
• feed additives, such as probiotics and other direct-fed microbials, and enzymes derived from
microbial cultures.
Supplements are usually mixtures of vitamins and minerals added to feed or drinking water. The
products can be formulated either as a dry powder mix or as a liquid preparation. Others are
formulated as self-administered products, such as solid salt or molasses block licks, or as liquid
licks. Some products are simply minerals, such as limestone and dolomite, which are mined out of
the ground, crushed, sieved and bagged as livestock mineral supplements.
Because of the large amount of dust generated during the manufacture of dry preparations, special
attention should be paid to cross-contamination control, either by physical separation from other
aspects of manufacture or by effective dust extraction and hygiene.
Some preparations are referred to as ‘electrolytes’, and are mainly used to replace minerals and
other electrolytes lost by greyhounds and horses during exercise. Despite the therapeutic claim, most
of these ‘electrolytes’ are more appropriately thought of as feed supplements from a manufacturing
point of view.
A6-002 Cleaning programs should specifically address the buildup of dust, sticky materials such as
molasses and corrosive materials such as salt.
A6-003 The manufacture of premixes often requires the use of large quantities of vegetable matter,
which is likely to attract insects, birds, rodents and other pests. This should be addressed in
the pest control program.
A6-004 External driveways and paths surrounding the manufacturing area should be sealed to
prevent the tracking of dirt and mud on the wheels of forklifts and other mobile equipment
into the production areas.
Personnel
A6-005 Where premixes and supplements are manufactured in premises also used to manufacture
other products, the staff involved in the manufacture of premixes and supplements should
be clearly identified and trained in those elements of GMP appropriate to their need.
Equipment
A6-006 Complete cleaning may not be required between batches of the same or closely related
products, provided that product integrity is maintained.
Process control
A6-007 Parts of the process likely to have a significant adverse influence on the stability of the
active ingredients (e.g. use of steam in pellet manufacture), should be controlled to ensure
batch-to-batch consistency.
A6-008 Special attention needs to be paid to the prevention of microbial contamination during
manufacture or storage of susceptible liquid formulations.
The identity and, where relevant, purity of the material being mined and of the processed material,
should be checked using an appropriate level of testing, consistent with registered particulars. Care
should be taken to ensure that stockpiled material is stored in such a way that contamination by
stormwater runoff and other drainage materials is avoided, and that the bagged material is free from
contaminants, such as pieces of metal, broken glass, bird and other animal droppings.
Enzyme feed additives are specific, naturally-occurring enzymes that are usually derived from cultures
of microorganisms similar to those used to manufacture direct-fed microbials, although some of them
are derived from plant or animal tissues. They are usually formulated as a powder or pellet, although
they can also be formulated as a liquid, and are usually added to stock feed as an aid to digestion
and to improve the efficiency of feed conversion.
Direct-fed microbials and enzyme products are susceptible to microbial contamination during
manufacture and subsequent storage and, in the case of enzyme products, heavy metal
contamination from materials used in the fermentation process. For APVMA registration purposes,
both types of products are required to meet minimum standards of potency, purity and activity of
the active materials and to be free from or meet required standards for harmful organisms such as
Escherichia coli and Salmonella spp. Enzyme products are also required to meet minimal standards
for heavy metal contamination.
Particular attention should be paid to the uniformity and quality of the parent material (master
and working seed cultures), media quality, and hygiene, both in the premises and during the
manufacturing process. There should be an adequate level of quality control testing during the
manufacturing process and of the finished product. A higher standard of manufacture is required
where the manufacturing process involves fermentation and/or extraction of culture.
Where the product being made is essentially a premix of the active material with other materials, the
standard of manufacture is essentially the same as that required for premixes and supplements, with
particular attention being paid to sanitation and the quality of the raw materials.
Personnel
A6-010 Personnel responsible for the manufacture and quality of direct-fed microbials and enzyme
products should have appropriate qualifications in microbiology or related subjects and/or
experience in the manufacture of such products.
A6-011 Where manufacture of direct-fed microbials and enzyme products is carried out in premises
also used to manufacture other products, the staff involved in the manufacture of direct-fed
microbials should be clearly identified and trained in those elements of GMP appropriate to
their need
Process control
Materials control
A6-012 The taxonomic identity of microorganisms selected for direct-fed microbials or enzyme
production should be checked.
A6-013 The master seed culture should be checked for identity by morphological characterisation
and comparison with the taxonomic characteristics originally identified. Its purity should
be checked before transfer to the fermentation equipment by serial dilution, plating and
macroscopic and microscopic inspection for any foreign microorganisms.
A6-014 The master seed culture should be maintained in such a way as to minimise degeneration
and maintain genetic stability.
A6-015 All seed cultures should be clearly labelled and strict aseptic techniques applied in revival
and subculture.
Production control
A6-016 All operations should be designed to avoid contamination, formation of undesirable by-
products, deterioration and handling errors.
A6-017 The culture liquid should be sampled and checked for purity at regular intervals throughout
the fermentation process. However, in semi-solid surface cultivation, purity control may be
restricted to visual inspection.
A6-018 Enzyme activity and operational parameters such as temperature, pH and oxygen content,
should be monitored during fermentation and kept within predetermined ranges based on
experience. Deviations from these ranges may indicate a contamination before it can be
detected in microbial assays.
Enzyme recovery
A6-019 Steps should be taken to ensure that contamination of the product during recovery
is minimised.
100 Australian Code of Good Manufacturing Practice for Veterinary Chemical Products
Glossary
Glossary
Please note: The definitions given below apply to the words as used in this Code of GMP. They may have
different meanings in other contexts.
Agvet Codes: the Agricultural and Veterinary Chemical Code in each state and territory of Australia
which, together with the Agvet Code Regulations, collectively form the legislative basis for the
operations of the APVMA throughout Australia. The Agvet Code may be found as a Schedule to the
Commonwealth Agricultural and Veterinary Chemicals Code Act 1994 as in force from time to time
(that is, including all subsequent amendments). The Agvet Code scheduled to the Agricultural and
Veterinary Chemicals Code Act 1994 applies to the Australian Capital Territory (including the Jervis
Bay Territory). Each state and the Northern Territory has enacted legislation (the Agricultural and
Veterinary Chemicals [State/Northern Territory] Act 1994) to apply the Agvet Code as in force from
time to time to that jurisdiction. The Agvet Code of each jurisdiction may collectively be referred to as
the Agvet Codes (see also Section 12 of the Agricultural and Veterinary Chemicals Act 1994).
Agvet Code Regulations: the Agricultural and Veterinary Chemicals Code Regulations 1995 as in force
from time to time, as referred to in the Agvet Codes.
Air lock: an enclosed space with two or more doors (only one of which is opened at any time), which
is interposed between two or more areas (e.g. of differing classes of cleanliness), for the purpose
of controlling the air flow between those rooms when they need to be entered. An air lock may be
designed for either people or goods; in the latter case it may also be termed a ‘pass-through hatch’.
An air lock may also be the ‘anteroom’ to a ‘cleanroom’ in which sterile goods are processed. It may
have an air supply which may be single-pass or recirculated.
Alert limit: established criterion (such as a microbiological count or a monitor reading), that gives
early warning of potential drift from normal conditions. Alert limits are not necessarily grounds for
definitive corrective action, but require follow-up investigation.
Approved supplier: a supplier of starting materials of known origin who is recognised as reliable,
based on a history of deliveries that all met specifications and were well packaged and intact on
receipt and, where possible, based also on a vendor audit.
Authorised person: a person recognised by the manufacturer as having the necessary basic scientific
knowledge and technical experience to carry out specified tasks associated with quality control. Note
that this definition is different from that given in the PIC/S code.
Batch: a defined quantity of material manufactured in one process or series of processes, from
the same initial starting materials, so that it might be expected to be homogeneous (i.e. uniform
with respect to composition and probability of chemical and/or microbiological contamination).
However, to complete certain stages of manufacture, it may be necessary to divide a batch into a
number of sub-batches, which are later brought together to form a final homogeneous batch. In the
case of continuous processing, the batch is an arbitrarily defined fraction of the production that is
characterised by its intended homogeneity (e.g. from one shift or one day, or derived from a particular
lot of active ingredient).
Australian Code of Good Manufacturing Practice for Veterinary Chemical Products 101
Glossary
Batch manufacturing formulae, manufacturing (or processing), and packaging instructions: are the
working documents associated with each batch of product manufactured. They are based on, and are
often authorised photocopies of, the master documents.
Batch number: a distinctive combination of numbers and/or letters that uniquely identifies a batch
during all steps in the manufacturing process.
• The batch number should allow a link to be established between the batch and all tests carried
out on it in the course of processing and quality control.
• A number of smaller batches may be combined by mixing to form a single batch. However, where
the bulk batch is divided into lots that are processed or packaged separately during the final
stage of manufacture, such lots should be distinguished from one another, for the purposes of
product labelling, by a suitable means (usually by an affix to the batch number).
• It is permissible to combine one unique series of numbers (processing numbers) on product
up to the point of packaging, and another for the packed product, with or without an affix as
described above), provided they are unambiguously correlated in batch records.
• It is also possible to combine a series of batches of bulk product into a continuous series of
packaging operations (not significantly separated in time, place or equipment) and apply a single
batch number to the packaged batch, bearing in mind that if a fault occurs, or reconciliation fails,
the whole series may have to be rejected or recalled.
• Incoming materials will usually carry the batch or lot number of their manufacturer, but will be
allocated a unique identifying number by which they are identified on the premises of the user.
This avoids the use of the term ‘batch number’ with two different meanings. Other in-house
terms for unique identifying number are acceptable.
Bulk product: any product that has completed all processing stages up to, but not including, final
packaging.
Calibration: the process of confirming that the values indicated by a measuring instrument or
measuring system, or values represented by a material measure, correspond with the known values
of a reference standard.
Clean area: a suite of rooms (cleanrooms) with defined environmental control of particulate and
microbial contamination, used in such a way as to minimise the introduction, generation or retention
of contaminants within it.
Code of GMP: the Australian Code of Good Manufacturing Practice for Veterinary Chemical Products. A
set of guidelines to assist manufacturers of veterinary chemical products to comply with the APVMA’s
Manufacturing Principles.
Contained area: an area constructed and operated in such a manner (and equipped with appropriate
air handling and filtration) so as to prevent contamination of the external environment by biological
agents from within the area.
Containment: the action of confining a substance within a defined space (e.g. carrying out dusty
operations in an enclosed room or containing spills within the confines of a bunded floor) or of
keeping pests, airborne materials and other contaminants out of a building by effective sealing of
entry points.
102 Australian Code of Good Manufacturing Practice for Veterinary Chemical Products
Glossary
Crude plant (vegetable drug): fresh or dried medicinal plant or parts thereof.
Document control: the process by which important documents are approved, identified, dated,
reviewed and updated as necessary, distributed on a restricted basis to where they are to be used
and controlled so that only the current version is available for use.
Filling: the process of filling primary packaging material with unprotected bulk product (e.g. filling a
bottle with liquid, tablets or capsules).
Finished product: a completed product which has undergone all stages of production, and which is
‘bottled’ or packaged, sealed and labelled.
Good manufacturing practice (GMP): a means of ensuring that veterinary chemical products are
consistently manufactured in a safe and clean environment, by specified methods, under adequate
supervision, with effective quality control procedures, so that the finished product meets the
standards of safety, identity, strength, quality and purity that it is represented to possess.
GMP Agreement: a written agreement between the primary manufacturer or registrant of a veterinary
chemical product (the contract giver) and another manufacturer or laboratory that carries out a
step in the manufacture of that product (the contract acceptor), that clearly specifies each party’s
responsibility in relation to every aspect of the manufacturing process, assurance of product quality
and product registration particulars.
Herbal medicinal products: medicinal products whose active ingredients are exclusively plant
material and/or vegetable drug preparations.
Intermediate product: partly processed material which must undergo further manufacturing steps
before it becomes a bulk product.
In-process control: checks performed during production in order to monitor and, if necessary, adjust
the process to ensure that the product conforms to its specification. The control of the environment
or equipment may also be regarded as a part of in-process control.
Manufacture: all operations (steps) involved in the manufacture of veterinary chemical products,
including purchase and quality assurance of raw materials, processing and blending or assembly,
quality control, packaging, labelling, sterilising and microbiological reduction, analysis and testing, in-
process storage, and releasing from manufacture for supply.
Manufacturer: any person (individual or legal entity) involved in any step of manufacture of a
veterinary chemical product.
Manufacturing premises: a place where any step in the manufacture of veterinary chemical products
is carried out.
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Glossary
Manufacturing Principles: a legal instrument to be made by the APVMA which defines the basic
principles that manufacturers of veterinary chemical products are required to comply with in order to
be issued with and retain a manufacturing licence under the Agvet Codes. These principles form the
basis of the Australian Code of Good Manufacturing Practice for Veterinary Chemical Products, with each
manufacturing principle corresponding with a key element of the Code of GMP.
Master document: a document from which copies are made for use in the manufacture or testing of
individual batches of product. The master is checked, authorised and filed until required for copying.
It is convenient to distinguish it by having some of the printing or signatures in red ink: the red colour
will not appear on copies.
Medicinal plant: a botanical plant, the whole or part of which is used for pharmaceutical purposes.
Packaging: all operations, including filling and labelling, which a bulk product has to undergo in
order to become a finished product. Note: sterile filling would not normally be regarded as part of
packaging.
Packaging materials: any material employed in the packaging of a veterinary chemical product,
including labels, but excluding any outer packaging used for transportation or shipment. Packaging
materials are referred to as primary or secondary according to whether they are intended to be in
direct contact with the product.
• primary packaging material—packaging material that comes into direct contact with the product
(e.g. a bottle or blister pack that contains liquids or tablets).
• secondary packaging material—packaging material that does not come into contact with the
product (e.g. a printed cardboard carton that encases a sealed and labelled bottle of liquid or
tablets).
Person responsible for production: the person nominated on the Manufacturer’s Licence as being
responsible for production.
Person responsible for quality: the person nominated on the Manufacturer’s Licence as being
responsible for quality.
Procedures: directions for performing routine operations, e.g. cleaning, clothing, environmental
control, sampling, testing, equipment operation. They are often referred to as standard operating
procedures (SOPs) or work instructions (WIs).
Qualification: the action of confirming that any equipment used or process step in the manufacturing
process works correctly and actually leads to the expected results. The qualification process can be
applied to equipment installation (installation qualification or IQ), equipment operation under different
operating conditions (operational qualification or OQ), or equipment operation as part of a specific
process (process qualification or PQ). Validation is often the sum of qualification steps.
104 Australian Code of Good Manufacturing Practice for Veterinary Chemical Products
Glossary
Quality assurance: is the sum total of the arrangements made to ensure that products are
consistently manufactured in an appropriate manner to the quality standards required for their
immediate use.
Quality control: is concerned with specifications, sampling and testing, and with the organisation,
documentation and release procedures that ensure that the necessary and relevant tests are carried
out so that materials are not released for use, nor products released for sale or supply, until their
quality has been judged to be satisfactory.
Quality control function: the procedures carried out by a manufacturer to ensure that effective quality
control is carried out at all stages of the manufacturing process and that the finished product meets
required specifications.
Quarantine: the status of starting materials, or intermediate, bulk or finished products that
are isolated, whether physically or by a system, while awaiting a decision on their suitability for
processing, or for sale and distribution.
Raw material: any chemical or physical substance used in the manufacture of a veterinary chemical
product, but not including packaging materials.
Reconciliation: the process of comparing, after making due allowance for normal variation, the
amount of product or in-process materials actually produced with the amount of starting materials
used, and the theoretical or expected amount.
Records: confirm that a particular procedure has been carried out correctly. Collectively, they
provide a history of each batch of product, including its distribution, and also of all other relevant
circumstances pertinent to the quality of the final product.
Reprocessing: the reworking from a defined stage of production of all or part of a batch of product
of an unacceptable quality so that its quality may be rendered acceptable by one or more additional
operations.
Secondary packaging: the process of placing filled, sealed, and labelled primary containers into an
outer ‘secondary’ container.
Specifications: describe in detail the requirements with which the products or materials used or
obtained during manufacture have to conform. They serve as a basis for quality evaluation. They may
include visual, organoleptic, physical, chemical and microbiological qualities.
Standard name: a name assigned to a starting material that uniquely identifies it within the
manufacturing establishment.
Starting material: any substance used in the manufacture of veterinary chemical products, including
both raw materials and packaging materials. (PIC/S definition is, ‘Any substance used in the
production of a medicinal products, but excluding packaging materials’).
Step of manufacture: a single, discrete manufacturing activity, e.g. quality assurance of raw
materials, blending, processing, primary and secondary packaging, labelling, analysis and testing,
sterilisation, release for supply.
Australian Code of Good Manufacturing Practice for Veterinary Chemical Products 105
Glossary
Sterile or sterility: freedom from viable contaminating microorganisms as described in the European
Pharmacopoeia or other acceptable contemporary standards. The level of assurance provided by the
absence of contamination in the sample, when applied to the quality of the batch, is a function of
both the efficiency of the sampling plan adopted and the rigour of the test methods employed.
Technical poison: any substance or preparation included in Schedules 6 or 7 of the Standard for the
Uniform Scheduling of Drugs and Poisons, published by the Commonwealth of Australia under the
Therapeutic Goods Act 1989.
Unique identifying number (UIN): a number allocated by the manufacturer to each ‘separate
material’ received onto the premises. Materials within the one delivery, but bearing different
manufacturers’ batch or lot numbers, should each be regarded as ‘separate materials’. In some
instances, allocation of the raw material manufacturer’s batch number may be acceptable.
Validation: the action of proving, in accordance with the principles of good manufacturing practice,
that any procedure, process, equipment, material, activity or system actually leads to the expected
results (see also qualification).
Veterinary chemical product: any substance that fits the legal definition of a veterinary chemical
product in the Agvet Codes.
Yield
106 Australian Code of Good Manufacturing Practice for Veterinary Chemical Products